|
University of California, San Francisco |  |
|
| |
|||
|
|||
|
||||||||||
Faculty of Graduate Group in Oral and
Craniofacial Sciences The mentors listed below are in alphabetical order, and you can use
the links to locate them by last name.
A |B |C |D |E |F |G |H |I |J |K |L |M |N |O |P |Q |R |S |T |U |V |W |X |Y |Z
Nina M. Agabian, Ph.D.
Microbial Pathogenesis
"Organisms which cause chronic disease have a unique relationship with
their environment. Whether a parasite, such as an African trypanosome,
or an opportunistic pathogen, like Candida albicans, each must evolve strategies for their
persistence, transmission and replication in either an immunocompetent
or immunocompromised host. Moreover, the pattern of gene expression can
vary significantly in the different microenvironments provided by
specific tissue and organ systems. Our laboratory is interested in
discovering and investigating the underlying mechanisms of pathogenesis
for both protozoan and fungal pathogens at the molecular and genetic
level. Most recently we have been using the genomic sequence derived
for the fungus, Candida
albicans to develop DNA
microarrays which will allow genome-wide expression analysis. For the
first time we are able to look at the interrelationships between genes
and biological pathways and to determine the patterns of
gene expression in different disease presentations, at lesions in
different
host tissues and to compare the human disease with that replicated in
relevant animal models. This technology is being applied to the
characterization
of virulence factors and mechanisms of pathogenesis for this
opportunistic
pathogen."
Tamara Alliston, PhD
One in three American adults suffers from arthritis symptoms,
yet the molecular basis of this degenerative skeletal disease remains
unclear. Our research focuses on the molecular pathways
controlling mesenchymal stem cell differentiation, how these pathways
function in normal skeletal tissue, and how they can be harnessed to
repair tissue damaged in degenerative skeletal disease. To answer
these questions, we combine molecular, cellular, physiological, and
materials science approaches. I believe this interdisciplinary
strategy will lead to the identification of targets to prevent skeletal
disease or to improve skeletal repair.
A current focus is to understand the mechanisms by which TGF-beta
regulates osteoblast and chondrocyte differentiation. Cell-based
studies are used to identify signaling pathways and transcription
factors downstream of TGF-beta. In vivo studies allow examination
of the role of these pathways in bone and cartilage. A key goal
of this work is to understand the control of skeletal matrix formation
and quality.
Gary Armitage, D.D.S., M.S.
"My current research interests include the development and testing of new methods for the diagnosis and treatment of periodontal diseases. Ongoing studies include evaluation of (1) microbial diversity in the subgingival flora, utilizing 16S ribosomal RNA gene detection techniques (in collaboration with Drs. David Relman and Paul Lepp of Stanford University); (2) salivary sialyl Lewis X in risk assessment for periodontal disease (in collaboration with Drs. Susan Fisher and Akraporn Prakobphol); (3) the effects of bisphosphonates and parathyroid hormone on mandibular bone density (in collaboration with Drs. Nancy Lane, Department of Medicine, School of Medicine, and Sharmila Majumdar, Department of Radiology, School of Medicine); (4) genetic tests for susceptibility to periodontal infections; and (5) drug-delivery systems for the treatment of periodontitis.
Research techniques routinely employed include (1) clinical research methods for the collection and analysis of periodontal examination findings; (2) gingival crevicular fluid analyses; (3) periodontal microbiology techniques such as the collection of subgingival plaque samples for microscopic, cultural, and molecular analyses; and (4) clinical trials and research study design."
Diane L. Barber, Ph.D.
"Our laboratory uses genetic and biochemical approaches to study the
signal transduction pathways used by hormone and growth factor
receptors
in regulating cell growth. Our recent focus is on receptor regulation
of
the GTPase family of proteins that control the organization of the
actin
cytoskeleton. Dynamic changes in the actin cytoskeleton play a critical
role in cell growth and differentiation, and we have determined that
these
dynamic changes are regulated by a complex interplay between adhesion
molecules
of the integrin receptor family, members of the Rho family of GTPases,
and plasma membrane ion exchangers. Most interesting is the novel
observation
that the link between adhesion receptors and cytoskeletal organization
requires
selective members of the family of plasma membrane Na-H ion exchangers.
We found that Na-H exchangers are structurally linked to the actin
cytoskeleton
through their direct association with ERM proteins of the protein 4.1
superfamily
of actin-binding proteins. Hence, plasma membrane ion exchangers can
link
the actin network to the plasma membrane and thereby convey input from
adhesion
molecules and GTPase signaling networks to the output of cytoskeletal
reorganization.
The functional significance of this interplay between integrin
receptors,
Rho family GTPases, and plasma membrane ion exchangers in cell
contractility,
migration, and proliferation is currently being investigated."
Lab web site
Charles N. Bertolami, D.D.S.,
D.Med.Sc.
Darren P. Cox, DDS,
MBA Oral pathology
Caroline H. Damsky, Ph.D.
"Our
research is directed toward understanding the roles of adhesion
receptors, primarily integrins, in regulating cell survival, tissue
remodeling and morphogenesis. In our studies of cell survival, we have
investigated the role of the integrin-activated focal adhesion kinase
(FAK) in regulating cell migration and survival. Using cells isolated
from FAK-null ES cells or embryos, we have shown that FAK
is required for survival following serum withdrawal. By comparing the
survival of cell lines that contain wildtype or mutated p53, we have
also determined that survival signals from matrix transduced by
integrins and FAK, suppress a p53-regulated apoptotic pathway (Ilic et
al, J. Cell Biol. 1998; Almeida et al., J.Cell Biol. 2000).
In studies related to tissue remodeling, in collaboration with Zena
Werb, we have shown that different integrins transduce signals that can
either stimulate or suppress matrix metalloproteinase (MMP) genes in
response to degradation fragments of the extracellular matrix (Werb et
al., 1989; Huhtala et al., 1995). Thus, in a tumor or chronic
remodeling environment, we propose that the presence of degraded ECM
can stimulate further elevation of proteinase expression, thereby
exacerbating tissue degradation and contributing to disease
(metastasis, arthritis) progression. We are currently testing this
hypothesis by expressing bioactive fragments of the ECM component,
fibronectin in osteoblasts of transgenic mice.
In studies of the role of adhesion receptors in morphogenesis, in
collaboration with Susan Fisher, we have determined that human
cytotrophoblast cells (CTB) adopt an vasculogenic phenotype during
their differentiation and invasion of the uterine wall and maternal
vasculature. As they differentiate and target maternal spiral
arterioles, they adopt the complete repertoire of endothelial adhesion
molecules and express receptors for vasculogenic and angiogenic
growth factors. Thus, it appears that a vasculogenesis program is
turned
on in the trophoblast lineage as well as in the endothelial lineage
(Damsky
and Fisher, Curr. Opin. .Cell Biol., 1998)).
Additional studies of integrin function address the role of
integrin-ECM interactions and downstream signaling by FAK in invasion
(Ilic et al., Am. J. Pathol., 2001), vasculogenesis and angiogenesis
(Ilic et al., Circ. Res., 2003), and osteoblast differentiation. In the latter case, we have established an
important role for fibronectin-integrin interactions in regulating
terminal differentiation of osteoblasts (Moursi et al., J. Cell Sci.
1996, 1997), and survival of mature osteoblasts (Globus et al., J. Cell
Sci. 1998). These results are being tested by establishing transgenic
mouse lines that express mutated integrins specifically in osteoblasts.
In our transgenic lines, expression of a truncated integrin beta 1
subunit leads to disorganized bone matrix deposition and excessive
remodeling by osteoclasts (Zimmerman et al., Dev. Biol., 2000). Currently, we are developing animal models with
osteoblast-specific knockout of FAK and integrin beta 1.
Thus,
we work in a variety of systems with the goal of understanding how
integrins and other adhesion receptors participate in the regulation of
complex cellular functions."
"The focus of research in my laboratory is in the biomineralization of
tooth enamel and dentin. We currently have several active projects to
study various aspects of enamel and dentin biomineralization. One of
these projects aims to determine the mechanism by which fluoride
affects enamel formation to result in enamel fluorosis. In this project
we are investigating several possible mechanisms by which enamel
fluorosis occurs, including altered
protein/mineral interactions, and a direct of fluoride on the
developing
ameloblasts.
In order to determine factors that alter enamel formation, we need to better understand the proteins, proteinases and other molecules responsible for normal enamel formation. We are using immunopertrubation and antisense methods in tooth organ culture to alter the presence of certain proteins in enamel development. These studies have suggested that the enamel matrix protein, ameloblastin, has a key role in the regulation of enamel matrix synthesis.
Our studies on dentin formation have utilized various
available transgenic mouse models with transgene expression driven by
the osteocalcin promotor. In one of these mice models that over
expresses TGF- , the dentin mineral apposition rate is increased while
the physical properties of the dentin remain the same. Studies of
dentin formation in these various transgenic mouse models will allow us
to determine the key elements in dentin biomineralization and to use
these elements to form dentin-like materials in vitro
."
Rik
M. Derynck, Ph.D.
"Our research focuses on the role of transforming growth factors- and , two structurally unrelated growth and differentiation factors, in mesenchymal and epithelial cells. We use molecular, genetic cell biological and biochemical approaches to address several cell physiological and developmental questions. The work has direct relevance to many questions in orofacial development and healing and is therefore of value to the proposed NRSA.
TGF- is a growth factor for many cell types of non-hematopoietic origin and exerts its functions in an autocrine/paracrine fashion mainly in normal epithelia and in solid tumor development. It is present as a transmembrane protein at the cell surface, from which the ecodomain can be proteolytically released as a secreted polypeptide. The transmembrane form of TGF- functions as a growth factor involved in cell-cell communication. Our major projects focus on the role of the cytoplasmic domain. We specifically study its ability to interact with cytoplasmic proteins that constitute an associated protein kinase complex and its potential role as a signaling entity, as well as its function in cell physiology and development.
TGF- is
a growth and differentiation factor which induces growth arrest in
epithelial cells, yet stimulates proliferation in mesenchymal cells,
and furthermore, is a potent inducer of extracellular matrix deposition
and integrin expression. TGF- is a prototype factor for the many related
differentiation factors in the TGF-
superfamily. Two major lines of research are followed. In one large
project, we address the mechanism of signaling of the TGF-
receptors, which are transmembrane serine/threonine kinases. In the
other major project, we study the role of TGF-
and vgr-1, a related factor, in mesenchymal differentiation,
specifically in differentiation into the muscle, bone and cartilage
lineages. These developmental questions are approached in cell culture
and in vivo ,
including transgenic models."
Lab web site
John D.B. Featherstone, M.Sc., Ph.D.
"I am currently involved in research in the following fields:
1. Effects of Lasers on Dental
Hard Tissues
The overall objective
of this research is to provide fundamental information about the
effects of laser light on dental hard tissues (enamel and dentin of the
teeth) in order to develop means of using lasers to a) detect early
decay, b) treat teeth and modify the mineral for the prevention of the
progression of dental decay.
2. Management of Dental Decay by
Risk Assessment
These studies involve
the application of microbiological and chemical assays of saliva as
part of a risk assessment scheme to enable the management of dental
decay by prevention and conservative treatment rather than conventional
physical removal of
decay and placement of restorations (fillings).
3. Biological mineral and protein
interactions
Biological mineral is a defective calcium phosphate crystalline
material. Studies of protein/mineral interactions are in progress
to understand the processes of biomineralization.
Susan J. Fisher, Ph.D.
"Our
major area of investigation is understanding adherence mechanisms used
by microbial pathogens. In one project we are testing the hypothesis
that
bacteria which colonize the oral cavity do so by interacting with the
carbohydrate portions of salivary receptors. In general, we use
whole-cell ligand blotting (overlaying blots of salivary glycoproteins
with bacteria) to identify interactions between individual salivary
molecules and particular bacterial species. This technique led to the
identification of a highly glycosylated, proline-rich glycoprotein
(PRG) as the major Fusobacterium nucleatum receptor in saliva. We then
determined, using mass spectrometry and nuclear magnetic resonance
spectroscopy, the complete structure of the subset of PRG
oligosaccharides that carry the bacterial receptor activity. We used
this same experimental strategy to study the interaction between
streptococci and the low-molecular-weight salivary mucin. Very recently
we showed that this glycoprotein carries sulfated sialyl Lex structures
and is a ligand for L-selectin. This observation has interesting
implications for leukocyte trafficking in the oral cavity."
Daniel Fried Ph.D.
"Optical or photonics based methods are playing an
increasingly important role in medicine and dentistry by providing a
means of minimally invasive diagnostics and imaging without the use of
ionizing radiation.
Projects include: the use of optical diagnostic tools such as optical
coherence
tomographic imaging, Raman scattering, IR and fluorescence imaging, and
time-resolved photothermal radiometry. In order to use lasers and
optical
diagnostic tools safely and effectively it is important to characterize
the optical properties of the tissue at the wavelengths of interest.
Therefore,
a major emphasis of my research has been on the accurate elucidation of
those properties."
Stuart Gansky, Dr.P.H.
Stuart Gansky's research has concentrated on collaborative
oral health research areas and its related methodological issues.
Collaborative research projects have included a series of studies
examining dentin, bonding, and tissue engineering; the
Intergenerational Study of Adult Periodontitis (MultiPied); the Study
of Chronic Pain/Temporomandibular Disorders (TMDs) in Young Women;
caries risk assessment studies (one on early childhood caries and one
on high risk adults); and tobacco cessation interventions.
He currently serves as Associate Director of the
Biostatistics and
Research Design Core of UCSF's Comprehensive Oral Health Research
Center of
Discovery as well as Director of the Measurement & Evaluation Core
of
UCSF's Center to Address Disparities in Children's Oral Health. He is
PI
of an NIDCR grant to develop risk assessment models for early childhood
caries. Also, he is co-PI and biostatistician to study factors
related to temporomandibular joint disorders and fibromylagia
precursors in an established cohort of young women in which racial
differences in pain reports have been found.
Barbara Gerbert, Ph.D
Dr. Gerbert has focused her research on the barriers to
optimal preventive health care and the role of health care
professionals. The research emphasizes the role of oral healthcare
providers and primary care physicians in providing preventive care in
the changing healthcare delivery system.
Harold Goodis, D.DS.
"My work focuses on the interactions between neurovascular modulators and inflammatory mediators; specifically prostaglandin E 2 (PGE2 ) and bradykinin (BK). The work allows me to use bovine and rat dental pulp for data collection with superfusion, radioimmunoactivity (RIA), and various blotting techniques. These techniques allow the study of the onset of neurogenic inflammation and the pain response in relationship to the release of peptides and the effect innocuous cooling has on their elaboration. Preliminary studies indicate that the neurogenic inflammatory response is related to the release of these peptides (PGE2 , BK).
The continued work using PGE 2 /BK combinations will lead to
the identification of the substances in the dental pulp that may be
responsible for acute and chronic inflammatory reactions. The addition
of RIA to my laboratory protocols has better define these interactions
and has allowed me to identify the BK B 2 receptor in rat dental pulp.
The identification of these receptors in bovine and rat pulp will lead
to their identification in human pulp and lead to development of a
model to further elucidate the different mechanisms involved in the
formation of the BK receptors, including the BK B 1 receptor, believed
to be involved in chronic inflammation and pain.
Recent work by other investigators has shown that fluid movement
through the dentin is related to dental pain, tooth sensitivity,
biocompatibility of dental restorative procedures, materials, and
medicaments, and the ability of restorative materials to form chemical
bonds to the dentin. Following this experience, I have shown that
dentin permeability in extracted teeth is extremely sensitive to
storage conditions, (medium and time) and that many
of the assumptions previously made need more careful consideration, as
shown
in my 1991 paper and several abstracts. This work is continuing and is
an
integral part of our funded program project grant, Dentin
Characterization and Modification. The work has been expanded in a
competitive renewal application to study permeability and other
mechanical, physical and chemical changes occurring in in vitro
transparent coronal dentin and root dentin. These studies are important
as altered forms of dentin resulting in changes in dentin fluid flow
and a diminishing pulp canal space may lead to an altered pain response
resulting in the need for interventions not presently a part of today's
techniques.
Taken together, the above work represents a focused investigation into
the biology of pain and inflammation in a unique tissue consisting of
primary afferent nociceptive neurons. It affords an opportunity to
develop alternative therapeutic techniques which will replace invasive,
pharmacological and non-reversible treatment modalities."
Deborah Greenspan B.D.S, D.Sc. (Med)
"My areas of interest include
clinical, laboratory, and epidemiological studies relating to the oral
manifestations of AIDS; the oral effects of cancer therapy; and the
development of new therapeutic approaches for oral mucosal and salivary
gland disease. I am part of a major epidemiological study of the oral
lesions of HIV infection and direct a
group of investigators identifying the oral lesions and providing
treatment
to people with these lesions. Some current studies include the
following:
the prevalence, incidence, and predicators of oral lesions in women
with
HIV infection (as part of the Women's Interagency HIV Study -WIHS), and
the
changing patterns of oral disease in the era of highly active
antiretroviral therapy in different HIV-positive populations. In
addition, I am collaborating with Dr. Francisco Ramos-Gomez (Dept. of
Growth & Development) on studies of injuries to dental heath-care
workers.
I am involved in several clinical drug trials, including the treatment
of aphthous ulcers, the treatment of oral warts, and the use of
antifungal medications in the treatment of oral candidaisis. In the
future, I plan
to continue with my work in all of these fields, to learn more about
the
significance of the oral lesions of HIV infection and to develop better
drugs for the treatment of a variety of oral conditions, such as oral
candidasis,
warts, xerostomia, and aphthous ulcers."
John S. Greenspan, B.D.S., Ph.D.
"My main research interest centers on the etiology,
pathogenesis, and management of oral soft tissue diseases, notably
those associated with HIV infection and other causes if
immunosuppression, as well as aphthous ulcers, Sjögren's syndrome,
and oral cancer/pre-cancer.
I serve as director of the Oral AIDS Center (OAC), which has been
supported by the NIDR. The OAC continues its research on the
pathogenesis of oral lesions associated with HIV infection. Dr. Joan
Hilton is responsible for the epidemiology portion of the OAC. Dr.
Hilton and myself, along with members of the OAC
are looking at the significance of oral disease in the progression of
HIV
infection. We are currently examining a large cohort of women for the
prevalence
of oral lesions such as hairy leukoplakia, aphthous ulcers, and oral
candidiasis. Dr. Joel Palefsky is leading a team research effort into
the molecular pathogenesis of EBV-associated hairy leukoplakia, and Dr.
Nina Agabian leads the candidiasis portion of the OAC's research
program. The OAC also conducts clinical trials of agents and modalities
to treat oral opportunistic infections, neoplasms, and
autoimmune/idiopathic lesions of HIV infection.
I also serve as Director of the UCSF AIDS Clinical Research
Center (ACRC). The mission of the ACRC is to provide clinical and
scientific leadership in a multidisciplinary response to the AIDS
epidemic in Northern California. Specifically, the ACRC has three main
objectives:
to facilitate the clinical care of HIV-infected persons in an academic
setting, providing a research infrastructure that will enable
epidemiological, clinical, behavioral, and basic research to be
conducted efficiently,
to promote pilot research projects into the pathogenesis, etiology, prevention, and treatment of HIV infection and its complication, and
to involve regional institutions and community-based
organization in the overall AIDS research enterprise in order to
maximize communications between scientists and care givers and to
foster collaborative research
with the community.
To facilitate the meaningful exchange between University researchers
and community groups, the ACRC maintains an active Community Advisory
Board, whose members participate in community outreach activities and
pilot grant review."
Carol A. Gross, Ph.D.
"My overall interest is to study
global regulatory networks in the bacterium E. co/i, which is amenable to both genetic and
biochemical approaches. We take two different approaches, each of which
illuminates this issue from different perspectives. First, we study the
heat shock response. This area of study has led us into a consideration
of how the cell monitors and regulates the folding state of proteins,
how proteins are targeted for degradation and how the cytoplasmic and
periplasmic compartments in K
co/i are coordinated.
Second, we study RNA polymerase, the enzyme responsible for
transcription, because it is the ultimate target of regulatory systems
that integrate intracellular and extracellular signals by adjusting the
transcriptional potential of the enzyme.
Our study of the heat shock response
has led us to find that K
coli mounts two
distinct responses to heat and other stresses: (1) a response measuring
conditions in the cytoplasm, which is orchestrated by the alternative
sigma factor a32, and (2) a response measuring conditions in the
periplasm, which is orchestrated by the alternative sigma factor aE.
Each response senses protein folding as well as other, yet unknown signals. We have defined the early events occurring in the cytoplasmic heat shock response and are now
investigating the molecular mechanism of these events. We have defined
many of the players in the periplasmic heat shock response and are now
defining the early events in this regulatory cascade, as well as using
this response as a entry point to understand how events in the
periplasm and cytoplasm are coordinated.
To understand how various cellular regulatory systems control RNA
polymerase, we first delineate the functional anatomy of the enzyme and
then investigate how altering its individual functions affects gene
regulation. Our study of RNA polymerase has shown that the sigma
subunit orchestrates initiation, that elongation and termination are
coordinated events and that, as judged by genetic criteria, conserved
regions of RNA polymerase contact each other. Current work in the
laboratory is focused on defining the conformational changes in sigma
throughout initiation, defining the sigma-core interface, investigating
the role of that interface in the transcription process, and
investigating the contribution of sigma affinity to global control of
transcription initiation. A second focus of our work is to define the
functional anatomy of core RNA polymerase by mapping interacting
domains of RNA polymerase and then determining the functional
significance of such interactions."
Charles Hoover, PhD
"My general research interests concern the etiology,
pathogenesis, and
treatment of oral microbial infections. My primary focus is the
application of molecular genetic techniques to investigate these issues
and the use of microbial colonization levels to monitor therapeutic
interventions, as well as to assess the risk of future disease.
Presently active independent and collaborative projects include (1) development of a conjugal E. coli-Porphyromonas gingivalis shuttle vector for use in genetic complementation (with Dr. David Corradi, Periodontology resident), (2) identification of oligosaccharide termini involved the in adherence of Candida albicans to salivary glycoproteins (with Dr. Susan Fisher and Asfoon Barkhordar, first-year dental student and summer fellow), (3) identification of oligosaccharide termini involved in the adherence of Helicobacter pylori to salivary glycoproteins (with Drs. Susan Fisher and Akaporn Prakobphol), (4) assessment of the role of Bacteroides forsythus components in bone nodule formation (with Drs. Peter Loomer and Ravi Smith, Periodontology resident), (5) evaluation of risk factors associated with the development of early childhood (baby bottle) caries (with Drs. Francisco Ramos-Gomez, Department of Growth and Development, and Stuart Gansky, Department of Dental Public Health and Hygiene), and (6) the effect of oral applications of plant-derived monoclonal anti -Streptococcus mutans antibodies on oral recolonization by mutans streptococci (with Drs. Jane Weintraub, Department of Dental Public Health and Hygiene; Joel White, Department of Restorative Dentistry; and Keith Wykoff, Planet Biotechnology).
Future projects include (1) a study
to
evaluate the effectiveness of ultrasonic lavage with a chlorine dioxide
mouthrinse (Cloysis II) in delaying recolonization by periodontopathic
bacteria (with Drs. Robert Wirthlin; Sophia Tseng, Periodontology
resident; and Perry Ratcliff, Rowpar Pharmaceuticals), (2) a study to
determine the benefits of caries management by risk assessment (with
Drs. John Featherstone, Department of Restorative Dentistry; Jane
Weintraub; and Joel White), and (3) a study to evaluate prevention and
treatment outcomes associated with early childhood caries (with Drs.
Jane Weintraub, Francisco Ramos-Gomez, Stuart Gansky, and John
Featherstone)."
Susan
Hyde, DDS, MPH, PhD
Epidemiology and gerontology
Richard Jordan, D.D.S., Ph.D.
"The focus
of my translational research program has been the characterization of
molecular events that occur during the progression of oral precancer to
oral cancer centered on how molecules, that normally regulate cell
proliferation, become dysregulated and thereby contribute to the
neoplastic phenotype. My research work, to date, has been the
application of molecular markers to clinical biopsy material obtained
from patients with oral precancer and cancer. My group was the first to
characterize changes in critical cell cycle regulators including p27kip1 and skp2 in
oral precancer and cancer. We were also the first to show
differing patterns of p53 protein expression in oral precancer and to
full-describe changes in the entire p53 gene in
head and neck cancers and impact on radiation therapy. We have
also characterized alterations in the CDKN2A gene
in oral precancer and cancer using state-of-the-art molecular pathology
methods such as laser capture microdissection (LCM) and real-time,
reverse transcriptase PCR. We were also the first group to define
changes in a key regulator of the p53 tumor suppressor gene, p14ARF in the
development of oral cancer. Another similar area of investigation
has been the application of these studies to chronobiology, the study
of
biological events over 24 hours, where we have demonstrated a circadian
pattern
in oral epithelial proliferation and the expression of cyclin proteins
and
clock genes."
www.ucsf.edu/oralpath
Arnold Kahn, Ph.D.
"For
about the past 150 years, the number of 65 year old + individuals in
the United States and the advanced countries of the world has steadily
and dramatically increased meaning that more and more individuals are
now experiencing the diseases and disorders commonly associated with
old age. These diseases/disorders include but are not limited to
osteoporosis, osteoarthritis, hearing loss, cataract and loss of
cognitive ability. Consequently, it has become increasingly imperative
to learn more about the aging process and how this process is linked to
the increased incidence of a particular subset of diseases and
disorders. The ultimate goal is to use this information either to
prevent these diseases/disorders from occurring or substantially delay
their onset, thereby assuring “healthy aging”. My research has
three components, each at a different stage of development. The first,
and most advanced of these
is to identify and employ markers of the aging process found in dental
hard
tissue and bone. Such markers are essential to objectively determine
the
state of aging of experimental animals or human subjects, and to assess
the
efficacy of interventions that might delay or prevent old age
associated-disease. The data, to date, confirm that secondary
dentin formation has utility as a measure of age in human subjects but
more importantly may also provide information on systemic disease or
senescent change (e.g., atherosclerosis, hypercholesterolemia).
Similarly, the loss of alveolar bone may also be a quantifiable
indicator of the physiological aging process but appears to be
unassociated with bone loss observed elsewhere in the aging
skeleton.
In addition to work on markers of aging, efforts are also underway to
become more fully engaged in a multi-center initiative (the Longevity
Consortium) aimed at identifying genes important in determining life
span and the risk of old-age associated diseases/disorders in
humans. Efforts, to date, have included analyses of TGF-b
polymorphisms (paper published) and alleles in the interleukin-1 gene
family
(MS in preparation) but future work will focus on genes in the
insulin/IGF-1
pathway and involved in stress resistance. The latter work will be
linked,
it is hoped, to the use of computer-based simulations of metabolic
pathways
to better identify candidate genes for analysis in future genetic
epidemiology
studies and/or experiments in animal models or in vitro. The current plan is
to initiate pilot studies using the latter technology sometime in 2004."
Ophir Klein, M.D., Ph.D.
Our research is centered on understanding and treating the processes underlying craniofacial and dental malformations. Our main focus is the use of mice as a genetic model system to elucidate the mechanisms responsible for normal and perturbed development of teeth, facial skeleton, taste papillae, and other organs. Specifically, we are interested in the role of growth factor signaling and cell-matrix interactions in the formation of orofacial structures and in the regulation of adult stem cells in teeth.
Randall H. Kramer, Ph.D.
"Our research is directed at
understanding how adhesion receptors regulate cell-matrix interactions
and what signals promote cell survival and growth. The first project is
testing whether integrins and growth factor receptors coordinately
regulate epithelial cell motility, invasion and proliferation. In
addition, we are exploring the specific downstream signaling events
initiated by activation of growth factor receptors that promote
activation of focal adhesion kinase and integrin receptors and disrupt
cadherin junctions during tissue remodeling. Finally, we have found
that cadherins
generate signals that promote anchorage-independent growth and suppress
apoptosis.
The second research topic concerns the laminin-binding alpha 7 integrin
during skeletal and smooth muscle differentiation. The alpha 7 integrin
forms the myotendinous junction and human congential myopathy is caused
by mutation in the alpha 7 gene. Studies are underway using the alpha 7
gene promoter in order to understand how integrin expression is
developmentally
regulated. The alpha 7 integrin is alternatively spliced in its
extracellular
and cytoplasmic domains, and this developmentally regulated splicing
controls
the activation state of the integrin. The alpha 7 receptor and its
variants
are being characterized through molecular approaches to further define
how
receptor function is regulated."
John H. Kinney, PhD
Synchrotron based computed tomography and biomechanics of calcified
tissues.
Enamel proteins
Jon D. Levine, M.D., Ph.D.
"We are pursuing three major areas of
research. The first area is an investigation of mechanisms that mediate
transduction of painful stimuli in sensory neurons. Transduction for
both thermal and mechanical stimuli are investigated and mechanisms
underlying sensitization of primary afferent neurons are also studied.
The second messenger systems and ionic conductances affected during
sensitization are being determined. The modulation of transduction by
opioids is also being investigated, including the mechanisms underlying
opioid tolerance and dependence. Molecular biological, biochemical, in
vitro and in vivo electrophysiological and behavioral techniques are
employed. We also investigate CNS circuits that mediate analgesia.
Studies of these circuits involve analysis of sites in the CNS and
neurotransmitters involved. Our recent work has described novel CNS
circuits that contribute to analgesia. We evaluate neural and endocrine
contributions to inflammation and to the immune response. The circuits
and mediators that contribute to the expression of immune responses are
being analyzed. A negative feedback inhibition of the inflammatory
response that involves specific neural and endocrine circuits has
recently been discovered."
Peter Loomer, DMD, PhD
Bone remodelling, peridontal pathogenesis, implants
Francina Lozada-Nur, D.D.S., M.S., M.P.H.
"Currently, my research interests focuses on clinical
epidemiology; media literacy and video production as a new instrument
to teach oral health to children; and on the use of alternative
medicine to treat chronic oral conditions such as oral lichen planus,
and the burning mouth syndrome.
Clinical Epidemiology:
I am interested in looking at the role of hepatitis C
infection in the pathogenesis of oral lichen planus (OLP) as well as
the role of OLP in the prognosis of HCV disease
In addition, we are evaluating the prognostic value of routine testing
for mucous membrane pemphigoid and disease course.”
Mahesh Mancani, MD
My long-term
research goal has been to establish an interdisciplinary program to
treat
patients’ bone abnormalities with cell-based therapies. Towards this
end, my
lab is exploring the role of bone marrow stromal cells (BMSCs) in bone
formation and remodeling, focusing on ways to enhance normal bone
formation in
patients with bone deficits or with osteoporosis. We
are focusing on 2 areas: 1) developing
techniques to engraft BMSCs and engineer bone, and 2) describing the
role of
BMSCs in bone formation and repair.
Ralph Marcucio, PhD
“My research focuses on elucidating the molecular and cellular events that regulate development of the craniofacial complex. Currently, I am examining the molecular interactions among the forebrain, the adjacent neural crest mesenchyme, and the overlying surface ectoderm. I have demonstrated that signaling by the Sonic hedgehog pathway within the forebrain regulates the formation of an important signaling center that is located within the ectoderm covering the face. These disruptions created severe facial malformations that resemble Holoprosencephaly. This is a severe malformation sequence that affects the middle part of the upper jaw, the upper part of the face, the eyes, and the forebrain. We are currently working to determine the role of various other pathways during development of this region of the face in order to identify other signaling pathways that may be susceptible to perturbations that could create phenotypic change that relates to Holoprosencephaly. In related research, I am utilizing my knowledge as a developmental biologist to assess the mechanisms that underlie the regenerative potential that the skeleton possesses. I am studying the cellular interactions that occur at the site of a skeletal injury in order to elucidate the molecular signaling mechanisms that regulate skeletal repair.”
web site: http://orthosurg.ucsf.edu/orthotrauma/html/research_molecular.htm
Grayson W. Marshall, D.D.S., M.P.H., Ph.D.
"Currently my work is focused on structure- property relationships
of
calcified tissues, particularly enamel and dentin, and cementum, to
improve our basic understanding of these biological materials
with respect to their mechanical behavior, and demineralization
processes associated with
bonding procedures and pathology. We use a variety of complimentary
techniques
some of which are nearly unique to our group (x-ray tomographic
microscopy;
atomic force microscopy (AFM); and AFM-based nanoindentation) as well
as
other complimentary methods including wet SEM and x-ray microanalysis.
We
have pioneered several of these methods for the study of calcified
tissues, and dentin in particular, and used the AFM to for the first
demineralization rate studies, the first nanomechanical properties
studies, and have obtained high resolution non-invasive images of
caries and dentin that allows the study of the three dimensional
structure of caries attack on tooth structure. This work helps define
alteration in properties and structure with hydration state, mineral
state, and variations induced by disease and physiological processes.
This information is needed to develop a composite structural model
of calcified tissues and to provide fundamental information needed for
tissue
engineering."
Sally J. Marshall, Ph.D.
"My research interests center on understanding the relationship between structures, properties and mechanisms in materials. My major expertise is in x-ray scattering, particularly diffraction, by materials and atomic force microscopy for microstructural and mechanical properties characterization. The nanostructure and properties of the interface between materials and calcified tissues are of great clinical significance since failure occurs in the weakest area of this structure. My current research efforts are mainly focussed in 2 areas: dentin characterization and modification, including the dentino-enamel junction, and the development of new dental implant material systems .
Much of dental materials research
involves attempts to improve bonding to dentin. Through collaborative
efforts with scientists at Lawrence Livermore and Lawrence Berkeley
National Laboratories, we are characterizing dentin, structurally and
chemically, with the premise that developing materials to bond to this
substrate will be greatly hampered until the substrate is understood.
We began by studying normal coronal dentin and have progressed from
normal dentin to altered forms of dentin, including transparent dentin
related to disease, age and intratooth position. We are using atomic
force microscopy to study morphological changes in dentin as a function
of drying, storage and demineralization. Demineralization is related to
the caries process as well as being a critical part of preparation for
bonding. The AFM is used to measure the nanoscale mechanical properties
of dentin and its interface with restorative materials. These
measurements are being combined with a model of dentin to predict
properties on the macroscale. We use x-ray tomographic microscopy, a
3-D non-invasive imaging technique developed by a colleague at LLNL, to
study morphological and mineral density changes as well. We have begun
a new project that uses the DEJ as a model interface between 2
materials with different mechanical properties. We
are beginning by studying the structure and using fracture mechanics to
determine the mechanical properties of the DEJ.
My
second area of interest is in the area of ceramic coatings on implants.
We are working with colleagues from LBNL to develop a new apatite based
bioactive coating that will more permanently adhere to Ti and Ti
alloys."
Jeffery N. Martin, MD, MPH
My work focuses broadly in the area of infectious diseases
epidemiology and specifically in the fields of human herpesvirus 8
(HHV-8) and HIV infection. In the realm of HHV-8, a primary goal is to
understand the specific route of viral transmission both in non-endemic
settings (such as the U.S.) and endemic settings (such as Africa).
Implicit in this work is understanding viral shedding among infected
persons. In this regard, saliva is now known to be the body fluid that
most commonly harbors HHV-8 and hence understanding the determinants of
viral shedding is a major goal. My interest in HHV-8 extends to the
disease it causes, Kaposi's sarcoma, where my group's work in Africa is
studying optimal approaches to treatment. In the field of HIV, I am
involved in several prospective cohort studies, both in the U.S. and
Africa, in which the focus is on translational research related to
pathogenesis and response to treatment. In addition to my research, a
considerable area of focus is on the development of clinical research
training. As Director of the UCSF Training in Clinical Research (TICR)
Program, I oversee curriculum development in a broad array of topics
related to epidemiology and biostatistics in the context of both
observational and experimental study design.
Robert
Messing, MD
web site: http://www.galloresearch.org/site/MessingLab/
Arthur J. Miller, Ph.D.
Joel M. Palefsky, M.D.
"Our ongoing projects fall into two main categories: 1)
control of DNA tumor virus replication and clinical manifestations of
DNA tumor virus infection in the setting of HIV-related
immunosuppression, and 2) biology of DNA tumor virus-associated
epithelial neoplasia.
Human papillomavirus: My group conducts studies characterizing the
natural history and pathogenesis of HPV infection and HPV-associated
neoplasia in HIV+ men and women. Pathogenesis studies include
investigation of cell-mediated immune response and characterization of
cellular genetic changes in HPV-associated lesions.
We are also investigating the role of calcium regulation proteins in
the immune response to HPV and HPV-induced transformation, as well as
stromal growth factors and cytokines. Finally, we are investigating
novel gene
therapy approaches to the treatment of HPV-related neoplasia that take
advantage of virus-specific gene targets.
Epstein-Barr Virus : My program on Epstein-Barr virus, like the HPV
program described above, is focused on epithelial infection. We have
characterized EBV gene expression in a unique EBV-associated epithelial
lesion that occurs in immunocompromised patients known as hairy
leukoplakia (HL). We are characterizing expression and function of
novel EBV
proteins that play a role in the pathogenesis of epithelial
infection. As in our studies of HPV, we are examining the role of
calcium regulation proteins in the immune response to EBV and their
effect on EBV replication."
Lenore P. Pereira, Ph.D.
"Our research has evolved
from studies on herpesvirus glycoproteins, to infection of polarized
epithelial cells and viral infection during pregnancy. Current projects
investigate CMV infection of the placenta that functions as a site of
viral infection and transmission to the fetus. We found that CMV
replicates in cells of the placenta called differentiating
cytotrophoblasts, impairs their invasion and
downregulates key adhesion and immune molecules required for proper
development. Moreover, CMV-infected endothelial cells transmit
infection to placental cytotrophoblasts supporting evidence that
infection small blood vessels become infected in vivo. Together these
findings suggest defects in formation of hybrid fetal-maternal
vasculature in the uterus could decrease blood flow to the fetus
causing
intrauterine growth restriction. Using microarray analyses, we are
identifying
viral genes that dysregulate cytotrophoblast differentiation, invasion
and
immune functions. We are also exploring the role of immune molecules,
in
particular human and viral interleukin-10 that reduce the functions of
matrix
metalloproteinsases. Failure of infected cells to degrade the
extracellular
matrix impairs endothelial cell migration and invasion of
differentiating
cytotrophoblasts in vitro. With regard to routes of CMV transmission to
the fetus, we found that the uterus serves as a virus reservoir and
that
replication in the decidua correlates with transmission of infection to
the adjacent placenta. Our results suggest that co-infections could
elicit
an inflammatory response that undermines placental development. Using
PCR
and immunohistochemistry, we identified CMV, herpes simplex virus and
bacterial
pathogens associated with premature labor are present at the
maternal-fetal
interface in early gestation. Current studies examine infections in
this
microenvironment and their involvement in pregnancy complications at
midgestation,
an issue of critical importance to prenatal development."
Ove A. Peters, PD Dr med dent, MS
Until recently, my primary research interests addressed
clinical
questions in endodontic therapy such as effects of root canal
preparation
on canal geometry measured by micro CT, physical parameters of
Nickel-Titanium
alloy in continuously rotating root canal instruments and antimicrobial
efficacy
of endodontic procedures . Presently, I am developing a second line of
research
that builds on several projects that I was also involved with in the
past
and addresses some issues in neurobiology and immunology: regulation of
chronic
inflammation, effect of inflammatory mediators on hard tissue
metabolism
and diagnostic parameters of pulpitis
"The main project in the laboratory involves evaluating the expression of tenascin-C (TN-C) during the progression of oral cancer. We have shown that TN-C is highly expressed in oral squamous cell carcinoma whereas only trace amounts can be identified adjacent to the basement membrane in normal oral mucosa. In mild to moderate dysplasia, expression of TN-C is similar to that found in the normal oral mucosa. However, in carcinoma in situ, TN-C expression is detected throughout the tissue stroma.
To examine the organization of TN-C matrices in vitro, we are using oral squamous cell carcinoma (SCC) cell lines and peritumor fibroblasts (PTF) isolated from biopsies and head and neck dissections. We have shown that several different oral cancer cell lines and PTF secrete a soluble form of TN-C, but are unable to organize a TN-C matrix in vitro. However, when co-cultured with oral SCC cells, the PTF assemble a TN-C matrix. Oral SCC cell conditioned medium does not induce the PTF to organize a TN-C matrix, but medium conditioned by both the oral SCC cells and the PTF can induce TN-C matrix organization by the PTF. TN-C matrix assembly is inhibited by antibodies to several integrin subunits as well as by antibodies to fibronectin. However, this inhibition can be reversed by first seeding the co-cultures on a pre-existing fibronectin substrate. We conclude that a fibronectin template is necessary for the SCC cell/PTF co-cultures to organize a TNC matrix, and that soluble factors secreted by both cell types are responsible for in vitro organization of TN-C matrices.
Another project in the laboratory involves
the differential expression of v integrins by highly and poorly
metastatic murine melanoma cells. We have found high expression of the
v 3 complex in the highly metastatic melanoma cells, but no expression
of the v 5 complex. In contrast, the poorly metastatic cells express
high levels of the v 5 complex, with
no expression of the v 3 complex. We are currently evaluating how
expression of 3 in the nonmetastatic cells affects invasion and
metastasis."
Francisco Ramos-Gomez, D.D.S. M.Sc., M.P.H.
"Dr. Ramos's research focus is the surveillance and epidemiology of "children at risk". His clinical research concentrates on HIV-infected and immunocompromised children; very young children affected by caries; children suffering from abuse; and children who are underserved or who lack adequate access to oral health care services. He seeks to increase understanding of how the knowledge, attitudes, and behaviors of patients, their families, and their health-care providers affect health-care practices. These investigations are designed to determine predictor variables and prognostic indicators for specific health-care risk factors confronting children at risk, and to use these predictors to devise ways in which the dental health care community can make early diagnosis of problems faced by these children. This work is intended to lead to the introduction of prevention or effective intervention and early treatment measures, with the purpose of improving the quality of life for these young patients.
Dr. Ramos has made a number of contributions
within this field, addressing topics such as the diagnosis,
significance, and management of HIV-related orofacial soft-tissue
manifestations in children; indicators for the early identification and
effective treatment of children at risk for caries; prevalence and
treatment costs of nursing caries among children in Northern
California; the knowledge and behavior patterns of California dentists
regarding child abuse and neglect; and accidental injuries among dental
health-care workers. He is currently involved in research on the
prevalence and treatment of early childhood caries; the oral risks
factors faced by immunocompromised children affected by AIDS; and
caries patterns among Latino pediatric populations in the United States
and Mexico. "
John L. Rubenstein, M.D., Ph.D.
Genetic Regulation of Head Development
"The embryonic neural tube
differentiates into diverse structures depending upon their spatial
coordinates within
the embryo. The forebrain, which is at the rostral end of the neural
tube,
differentiates into the cerebral cortex, the basal ganglia and other
components,
each with distinct histologies and functions. The genetic program which
specifies
the developmental fate of different regions of the neural tube remains
to
be elucidated.
Our laboratory is interested in studying the genes that regulate
regional specification and differentiation of the mammalian forebrain.
In addition we are interested in the genetic control of craniofacial
development. To this end, we have identified several novel genes that
are candidates for regulating forebrain and craniofacial development.
We are focusing on two types of
transcription factors. One, named Tbr-1, encodes a homologue of
Brachyury,
that is expressed in the cerebral cortex, while the other, named Dlx,
encodes
a homeodomain that is expressed in craniofacial primordia and in the
basal
ganglia.
Analysis of the expression of these and related genes has proven to be
a useful method to define subdivisions of the forebrain. These studies
have led us to propose that the forebrain is subdivided by longitudinal
and
transverse boundaries, and thereby has a neuromeric organization. We
are
continuing these studies studying the inductive mechanisms that pattern
the neural plate and neural tube.
To determine the function of the
candidate regulatory genes, we have generated mice that have loss of
function and gain of function mutations. To study development the basal
ganglia and the face, we are analyzing the phenotypes mice that lack
function of several homeobox genes (Dlx-1, Dlx-2, Dlx-5 and Nkx-2.1).
To study development of the cerebral cortex, we are analyzing the
phenotype of mice that have mutations in other transcription factors
(Tbr-1, Emx-1 and Gbx-2). These investigations have demonstrated the
role of specific transcription factors in regulating neuronal
specification, differentiation, migration and axon growth.
In the long-term, we are interested in understanding the hierarchy of
regulatory genes that orchestrate development of the forebrain and the
face. To this end, we have begun to search for: (1) the proteins that
regulate Dlx expression; (2) the targets of the DLX proteins; (3)
proteins that interact with the DLX proteins which modulate their
transcriptional activity. We would eventually like to integrate these
findings to better understand human developmental disorders."
Mark Ryder, D.M.D.
"The principal area of research in my laboratory is on the effects of tobacco smoking on neutrophil and monocyte function. These functional studies have employed flow cytometry, image analysis, enzymatic assays, ELISA, and microarrays to examine inflammatory and host response processes such as phagocytosis, oxidative burst, f-actin kinetics, chemotactic peptide binding kinetics, expression of selectins and integrins, cytokine release, and expression of m-RNAs.
Epidemiological evidence strongly suggests that tobacco use may be the most important preventable risk factor for periodontal diseases. Changes in the host response in general, and in neutrophil and monocyte function in particular may play a critical role in the pathogenesis of periodontal diseases in smokers. The studies in my laboratory on the effects of major components of tobacco smoke such as nicotine, cotinine, ammonia, benzene etc. have shed new light on the possible mechanisms of neutrophil and monocyte mediated destruction of periodontal tissues in smokers. Specifically, we have found that nicotine at low concentrations found in smoker's serum enhances the binding of chemotactic peptides.
In addition, in vitro whole smoke exposure appears to stimulate shedding of selectins and upregulation of integrins. These two phenomena may elevate the chemotaxis response resulting in an increased number of neutrophils in periodontal tissue. Once in the periodontal tissues, the neutrophils are exposed to higher levels of tobacco substances. My laboratory has shown that these higher levels of nicotine and other substances alter the kinetics of two critical intermediate steps in neutrophil function: F-actin polymerization/depolymerization and the intracellular release of calcium. Specifically, these substances appear to "freeze" these functions at an elevated level. These findings may be related to other observations made in our laboratory on tobacco related neutrophil functions including a dose related elevation in the oxidative burst and release of secondary granule contents but a dose related suppression of phagocytosis and release of primary granule contents. Our observations have several important implications in tobacco related periodontal diseases. Briefly, the increase in recruitment of neutrophils to periodontal tissues with an elevated oxidative burst and release of secondary granule contents can result in damage to healthy periodontal tissues. On the other hand, the suppression of both phagocytosis and release of primary granule contents (particularly myeloperoxidase- an important enzyme against the predominantly gram negative periodontopathic bacteria) can significantly impair the host response.
In the past several years, we have turned our attention to
the effects
of acute smoke exposure on a second critical component of the
inflammatory/host response, the monocyte. We have observed that
acute cigarette smoke alters the cytokine release profile of monocytes
from a more reparative/ regenerative profile (e.g. the suppression of
TGF-b release to a more destructive inflammatory profile (e.g. the
elevation of IL-1b release). These effects of cigarette smoke on
monocyte cytokines may also contribute to the increases in periodontal
breakdown in smokers. In the past year, through
a collaborative arrangement with the Cancer Center at Mt. Zion
Hospital, we
have examined the effects of smoke on the expression of monocyte
m-RNA¹s through microarray technology. The results of these
preliminary mocroarray studies confirm the findings from our previous
work on monocytes. In
addition, microarray analysis has revealed several
previously unreported changes in m-RNA expression in moncytes exposed
to smoke.
Peter B. Sargent, Ph.D.
"Our
laboratory is interested in the role that nicotinic receptors play in
synaptic transmission.
Nicotinic receptors are membrane-bound ion
channels that are gated by the transmitter acetylcholine (ACh) and also
by exogenous ligands, such as nicotine They
underlie rapid synaptic transmission at all synapses in the peripheral
nervous system. Within the central nervous
system, the diversity of
nicotinic receptor (AChR) expression and the widespread effects of
nicotinic agonists on behavior implies that these molecules are
involved in a host of functions, including attention, learning and
memory, and goal-directed behavior. Some
of the functions of AChRs have been attributed to their placement
presynaptically and their ability to modulate transmitter release,
while other effects are likely to be mediated postsynaptically.
To enhance our understanding of nicotinic
synaptic mechanisms we have studied transmission at a particularly
accessible cholinergic synapse in the peripheral nervous system: the
giant calyceal synapse in the chick ciliary ganglion.
This synapse consists of a single, large calyx terminating on a
dendrite-free postsynaptic neuron. At late
embryonic stages, the synapse is highly developed and allows the
postsynaptic neurons to follow presynaptic action potentials at
moderate to high frequencies. The
post-synaptic neuron is electrically compact, and whole-cell recordings
can be made both from it and from the giant presynaptic terminal. AChRs are found both postsynaptically, where
they underlie rapid synaptic transmission, and presynaptically, where
their function is not known.
In the ciliary ganglion we have used imaging
techniques and laser scanning confocal microscopy to examine the
distribution of AChRs on the surface of ciliary neurons, and
neurophysiological techniques to study the role that distinct classes
of AChRs play in synaptic transmission. We
have shown that ACh activates at least two different AChRs: those
containing a7 subunits (a7-AChRs)
and those containing a3 subunits (a3-AChRs). We have also shown that the distribution of
these AChRs is distinct: a3-AChRs feature prominently at synaptic sites
on the cell body, while a7-AChRs are found on collections of somatic
spines, some distance away. Current
efforts are directed at understanding the basis of a3- and
a7-AChR mediated synaptic currents.
In a related area, we have recently completed
a study of presynaptic AChRs located at the calyceal synapse in the
ciliary ganglion. We have used calcium
indicator dyes and real-time imaging to show that nerve released ACh
acts back on the presynaptic terminal to elevate the calcium
concentration. We will next test the
hypothesis that this feedback serves to enhance transmitter release
during bouts of high frequency stimulation, when release might
otherwise be depleted.
We have recently started to examine nicotinic receptors and synaptic transmission in mammalian autonomic ganglia and intend eventually to move from the chick model to the mammalian one. We have also extended our studies to nicotinic synaptic transmission in the central nervous system or rats. In a study recently published in J. Neurophysiol., we examined transmission in spinal cord slices from a-motor neurons to glycinergic interneurons known as Renshaw cells. Using immunofluorescence we showed that Renshaw cells express a4 and b2 AChR subunit immunoreactivities, and using whole-cell recording techniques we showed that that the receptors underlying motor neuron-Renshaw synaptic transmission have the pharmacological characteristics of a4b2-containing AChRs. These AChRs have a high affinity for nicotine and may be altered during chronic exposure to nicotine, as occurs during smoking. In a model for neonatal exposure to nicotine, we will be examining whether transmission onto Renshaw cells in rat pups is altered when their mothers are exposed chronically to nicotine."
Richard A. Schneider, Ph.D.
"I am studying molecular and cellular mechanisms of normal and abnormal facial development. My current work focuses on the regulation of cell differentiation. Disruptions to this process result in a range of human birth defects. For example, premature cell differentiation within the osteogenic front of cranial sutures causes craniosynostoses. Conversely, a delay in differentiation of median edge epithelium leads to clefting of the secondary palate. Thus, the timing of differentiation among multiple populations of embryonic cells is a prerequisite for normal facial growth.
In my ongoing research, I am investigating how cranial populations of neural crest, ectoderm, and mesoderm learn when to differentiate into discrete facial structures such as cartilage, bone, epidermis, and muscle. I hypothesize that neural crest cells regulate their own temporal differentiation as well as that of adjacent mesoderm and ectoderm. To test this hypothesis, I am performing a series of neural crest transplants between two distinct avian species, quail and duck. My approach exploits the fact that quail and duck have considerably different rates of maturation, which provides a novel method for identifying time-dependant interactions between neural crest and adjacent populations. Results from my research can reveal etiologies of human craniofacial birth defects and potentially lead to new treatment and prevention strategies."
Caroline Shiboski, D.D.S., M.P.H., Ph.D.
"As an assistant clinical professor with expertise in epidemiology and oral medicine, I am currently involved in several research projects on the topic of oral health and immunodeficiency. In the area of HIV-related dental public health, I am conducting a follow-up study to a survey on utilization of dental care among HIV-positive women participating in the Women's Interagency HIV Study (WIHS), which began in 1994. In the area of HIV-related clinical epidemiology, and with colleagues from the Oral AIDS Center, I am involved with two projects: (1) As a co-investigator in the Reaching for Excellence in Adolescent Care and Health (REACH) Project, the main objective being to investigate, among HIV-positive adolescents, the occurrence of oral mucosal disease in relation to selected biological, behavioral, and socio-demographic variables. (2) As a co-investigator in the HIV Oral Transmission (HOT) study, which takes as its main objective to identify risk factors for oral acquisition of HIV infection.
As an extension of my research activity in the area of oral disease in immunosuppressed populations, I am interested in oral disease among solid-organ transplant recipients. In 1998, in collaboration with colleagues from the Division of Periodontology (Dan Lauber) and from the School of Medicine (William Amend), I conducted a pilot study to investigate the natural history of oral mucosal disease and gingival enlargement in renal transplant recipients. I have presently applied for NIDCR funding to continue the study of this population. The objective of the proposed 5-year study among these patients is to investigate the long-term side effects of corticosteroids and new-generation immunosuppressants on the incidence of oral soft tissue disease and on changes in mandibular bone structure. A secondary goal is to determine whether change in the fractal dimension of mandibular bone predicts change in bone mineral density of various skeletal sites, and whether it may be used as a diagnostic tool to detect osteoporosis in this high-risk population of transplant recipients."
Michal Staninec, DDS, PhD
Clinical research on new dental materials and procedures; mechanical
properties of dentin; bonding to laser-irradiated tooth
surfaces
Antoni P. Tomsia, Ph.D.
Glass material seals; hydroxyapatite coatings on titanium alloy
implants.
"Our clinical research is focused on 1) characteristics of
growth and development in cleft lip and palate, hemifacial microsomia
and craniosynostosis syndromes, 2) delineation of factors contributing
to abnormal development, 3) effects of the neuromuscular system on bone
morphology and growth patterns under normal and perturbed conditions,
4) stability of craniofacial skeletal components after major
reconstructive procedures, and 5) treatment outcomes following various
types of management procedures in a team environment."
Jane A. Weintraub, D.D.S.,
M.P.H.
Dr. Jane Weintraub is the Lee Hysan Professor of Oral Epidemiology and
Dental Public Health and Director of the NIH-funded Center to Address
Disparities in Children’s Oral Health (called the CAN DO Center).
Dr. Weintraub's research has focused on the epidemiology of oral
conditions, the prevention of dental disease, and the evaluation of the
effectiveness of dental programs and treatments. Most recently, she has
been involved with clinical and community-based research to assess the
efficacy or effectiveness of a variety of caries preventive methods
including dental sealants, fluoride varnish, and combined caries
management techniques. The goal of the CAN DO Center is to
prevent and reduce oral health disparities, with a focus on preventing
early childhood caries. Please see the CAN DO website for more
details. http://www.ucsf.edu/cando/
Dr. Weintraub, a board certified public health dentist,
is currently the President-elect of the American Association of Public
Health Dentistry.
Zena Werb, Ph.D.
"All cells in multicellular organisms are in contact with the extracellular matrix (ECM), which provides mechanical support, spatial cues and signals to regulate differentiation, proliferation and apoptosis. We are investigating the signal transduction mechanisms initiated by ECM, and how these pathways intersect with signals from growth and differentiation factors. We want to know how ECM, in cooperation with growth factors, mediates growth, differentiation, remodeling, cell migration, tissue invasion, and morphogenesis. As the cells change in response to ECM they also change their morphology and cytoskeletal organization. We are using two systems to elucidate these mechanisms.
Fibroblasts exist in either a
quiescent state or in an activated migratory and tissue-remodeling
state characteristic of wound healing. The composition of the ECM seen
by the fibroblasts regulates these two states. The genes encoding
ECM-degrading matrix metalloproteinases are upregulated in the
activated fibroblasts by a signal transduction cascade initiated by
integrins. We have begun to elucidate the kinase cascade activated by
binding to integrins, resulting in activated transcription factors
binding to promoter sequences in ECM-responsive genes. It is now clear
that there are four distinct signaling pathways mediated by adhesion,
that result in organization of focal adhesions, alteration in cell
shape and migration, endocytosis and signaling for proteinases and
their inhibitors. The molecular mechanisms involved in these distinct
pathways are now being elucidated.
We
want to understand how ECM diversity orchestrates changes in gene
expression. It appears that several ECM receptors process extracellular
information cooperatively, in collaboration with receptors for growth
factors. We also need to elucidate what role the cytoskeleton plays in
the processing of ECM information."
Joel White, DDS, MS
Clincal research on lasers and dental procedures
Torsten Wittmann, PhD
My research program focuses on the function and spatiotemporal regulation of the microtubule cytoskeleton during the establishment and maintenance of cell polarity and other complex cell behaviors. Although actin polymerization dynamics and myosin-mediated contractility provide the force for cell shape changes, microtubules are fundamentally important for planar cell polarity and directed migration.
Microtubules are dynamic polymers that in cells frequently switch between polymerization and depolymerization. The idea that this non-equilibrium behavior allows microtubule ends to explore the cytoplasm to find and interact with specific targets is not new. However, this search-and-capture hypothesis has regained vigor by the discovery of a heterogenous group of proteins, referred to as +TIPs, that are functionally defined by their dynamic localization to growing microtubule ends in cells. The molecular functions of this microtubule plus end complex are not well understood. My laboratory uses classical biochemical techniques in combination with advanced live cell fluorescence light microscopy to examine the molecular mechanisms by which microtubules, +TIPs, and other cytoskeletal proteins determine cell behavior. Currently, our major experimental model system are planar polarized human keratinocytes that directionally migrate at the edge of an epithelial cell sheet. We will extend our studies into other tissue culture systems such as apical-basal polarized epithelial cells and endothelial cells that establish planar polarity in response to fluid shear stress.
http://www.ucsf.edu/~wittmann/
