UCSF News ALS Research Center
350 Parnassus Ave., Suite 500B - Catherine Lomen-Hoerth, M.D., Ph.D.
Clinical research includes investigator initiated projects and participation in multicentered treatment trials. Investigator initiated projects typically utilize clinical neurophysiologic techniques to define the pathophysiology of disease or clinical subtypes that may respond differently to treatment. Representative recent publications are as follows: Integrity of Spinal Motor Neurons Receiving Dysfunctional Corticomotoneuronal Projection in Amyotrophic Lateral Sclerosis. Neurology 1996;47:1555-1561. Longitudinal study of fiber density and motor unit number estimate in patients with amyotrophic lateral sclerosis. Neurology1997;49:573-578. Recent multicentered, double-blind, placebo-controlled trial participation includes: neurotrophin-3 (NT-3) and nerve growth factor (NGF) for diabetic polyneuropathy, peptide T and lamotrigine for painful neuropathy associated with HIV, and gabapentin for ALS. Current compansonate-use, early-access participation includes Myotrophin (IGF-1) and brain-derived neurotrophic factor (BDNF) for ALS. Participation in these activities is included in the Clinical Neurophysiology-Neuromuscular Diseases fellowship. For information call 415-476-7581.
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UCSF Behavioral Neurology Training Program
350
The Behavioral Neurology Training Program (BNTP) at UCSF School of Medicine focuses upon the diagnosis and treatment of degenerative dementias. In addition to Alzheimer's disease, patients with frontotemporal dementia, semantic dementia, dementia with Lewy bodies, Creutzfeldt-Jakob disease, multi-infarct dementia, Huntington’s disease, progressive supranuclear palsy, and corticobasal degeneration are seen. Each disorder has an unique anatomic and neurochemical profiles which predict the clinical features of the individual patient. The effects of these disorders on memory, language, visuospatial skills, social behavior and cognition are studied with neuroimaging and neuropsychological testing (including experimental cognitive paradigms). UCSF has been designated a national Alzheimer’s Disease Research Center (ADRC). NIH-funded research projects are available to interested participants.
For information please visit the Memory & Aging Center website, call (415) 476-6242, or email bntp@memory.ucsf.edu.
Neuro-AIDS Clinical Research
San Francisco General Hospital - Richard Price, M.D., Cheryl Jay, M.D. and Serena Spudich, M.D.
This one- or two-year position is designed to provide clinical and clinical research training in the neurology of HIV infection and AIDS. Fellows will train in the evaluation and management of patients in the in- and out-patient settings in order to attain an in-depth experience in clinical issues of HIV neurology. Individual research projects will center on: the dynamics of cerebrospinal fluid (CSF) HIV infection and local host responses, the impact of primary HIV infection on the central nervous system, clinical trials of novel therapies on CNS infection and injury, and neurological disease in resource-poor settings, including Africa. These studies include active collaborative studies with the clinical HIV, virology and immunology programs at San Francisco General Hospital and UCSF. This clinical research fellowship may also be combined with a thematically related laboratory experience over a longer time period. Representative papers include: Price RW, Deeks SJ: Antiretroviral Drug Treatment Interruption in HIV Infected Adults: Clinical and Pathogenetic Implications for the Central Nervous System, J Neurovirol, 2004, 10 (suppl 1): 44-51. Spudich, SS, Huang, W, Nilsson, AC, Petropoulos, CJ, Liegler, TJ, Whitcomb, JM, Price, RW. HIV-1 chemokine co-receptor utilization in paired cerebrospinal fluid and plasma samples: a survey of subjects with viremia, J Infect Dis , 2005, 191:890-898. For information call (415) 206-3207.
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Clinical Neurophysiology / Neuromuscular Diseases
Moffitt-Long Hospital - Catherine Lomen-Hoerth, M.D., Ph.D.
This one- or two-year position is aimed at providing a broad education in the clinical, electrodiagnostic, and pathophysiological aspects of neuromuscular diseases. It also provides broad coverage of clinical neurophysiology so that fellows are eligible for examination by the American Board of Psychiatry and Neurology for added qualifications in clinical neurophysiology, as well as by the American Board of Electrodiagnostic Medicine. There is exposure to a wide variety of neuromuscular diseases and to the most advanced neurophysiological techniques for the evaluation of neuromuscular disorders. Ongoing research is directed at therapy of ALS by various neurotrophic factors, clarifying the clinical utility of motor unit number estimation, and evaluation of long loop reflexes. Representative publications are as follows: The electrophysiologic features of sciatic neuropathy in 100 patients. Muscle Nerve 18:414-420, 1995. Late electromyographic activity following stretch in human forearm muscles: physiological role. Brain Res 641:273-278, 1994. For information call 415-476-1986.
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Ernest Gallo Clinic and Research Center
For information about fellowships, please visit the Ernest Gallo Clinic and Research Center career page.
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Gladstone Molecular Neurobiology Program
Mission Bay - Lennart Mucke, M.D.
Our research focuses on mechanisms of neurodegeneration with a particular emphasis on the molecular pathogenesis of Alzheimer's disease and related neurodegenerative disorders. Potential etiologic factors and pathogenetic pathways are assessed in neural explant cultures as well as in genetically engineered mice (transgenics/knockouts) to identify critical targets for therapeutic interventions. Animal models are used to examine the relative efficacy and safety of novel treatment strategies aimed at the prevention or amelioration of central nervous system impairments. The relevance of results obtained inexperimental models is evaluated by comparative analyses of human postmortem tissues and clinical specimens. Our research strategy is multidisciplinary and involves diverse fields including molecular biology, biochemistry, signal transduction, pharmacology, immunology, histopathology, and behavior. For information please visit our web site or contact our Postdoctoral Advisor, John LeViathan, 415-734-2036.
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Molecular Neuroimmunology Laboratory
Moffitt-Long Hospital - Jorge Oksenberg, M.D.
The principal aim of our laboratory is to identify the major genetic factors that predispose to autoimmunity in the central nervous system and modulate disease presentation and progression. The availability of highly sensitive and high-capacity methods for analysis of gene variation and expression combined with the implementation of algorithms that predict behaviors in complex biological circuits provides an outstanding opportunity to facilitate progress in the integration of multiple data sources and functional interpretation of physiological and laboratory results. Our goal is to apply novel molecular, informatic, statistical, and epidemiological approaches to illuminate fully the genetics of autoimmune demyelination. Specifically, our research plan includes:
- Genome wide haplotype mapping in multiple sclerosis (MS)
- Large family-based and case-control studies of MS candidate regions and genes
- Genotype-phenotype correlations in MS
- Gene-environment correlations in MS
- Genomic and clinical study of MS populations at low and intermediate risk
- MS pharmacogenomics
- Functional genomics and proteomics
Representative publications:
- Baranzini S.E., et al. Transcription-based prediction of response to IFNß using supervised computational methods. PLOS Biol. 3(1)e2, 2005.
- Baranzini S.E., et al. Modular transcriptional activity characterizes the initiation and progression of autoimmune encephalomyelitis. J Immunol. 174:7412-7422, 2005.
- International Multiple Sclerosis Genetics Consortium. High density linkage screen of multiple sclerosis . Am. J. Hum. Genet. 77:454-467, 2005
- Haskin G., et al. Mapping gene activity in multiple sclerosis: Integration of expression and genomic scans. J Neuroimmunol. In press.
- Reich D.E., et al. A whole-genome admixture scan localizes a candidate gene for multiple sclerosis susceptibility. Nat. Genet. In press.
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Molecular Analysis of Neurotransmitter Release
Mission Bay Campus - Robert H. Edwards, M.D.
The regulated release of neurotransmitter underlies most forms of signaling in the nervous system. Changes in transmitter release contribute to neural plasticity, normal behavior and neuropsychiatric disease. However, the molecular basis of transmitter release remains poorly understood. The lab focuses on two main problems. First, how are neurotransmitters transported into secretory vesicles for release by exocytosis? Over the last ten years, we have identified three families of proteins responsible for transporting essentially all of the classical transmitters into vesicles. We are now studying their regulation by membrane trafficking to different populations of secretory vesicles, and by direct interaction with other vesicle proteins. The approaches range from electrophysiology to cell biology and genetic manipulation in mice. Second, what causes the degeneration of dopamine neurons in Parkinson’s disease? We have previously found that the vesicular monoamine transporter protects against an exogenous toxin and we are now extending the analysis to understand how it and related mechanisms may protect against the intrinsic toxicity of the normal transmitter dopamine. In addition, considerable work has implicated the presynaptic protein α-synuclein in Parkinson’s disease, and we are using biochemical approaches together with live cell imaging to understand its normal function and role in degeneration.
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Neonatal Brain Disorders Laboratory
Parnassus Heights Campus - Donna Ferriero, M.D.
The research is directed toward understanding the cellular and molecular mechanisms underlying hypoxic and ischemic injury to the developing brain. In the laboratory, we study the selective vulnerability of the immature nervous system in relationship to oxidative stress, neurogenesis and repair.
In particular we will continue to:
1) map selectively vulnerable regions after neonatal insults at different developmental stages;
2) correlate MR findings with neurodevelopmental sequelae - current projects include mapping corticospinal tracts with diffusion tensor imaging with neuromotor findings, and visiomotor with oculomotor development;
3) correlate neonatal and parental cytokine and coagulation and vascular abnormalities with patterns of stroke and outcome;
4) use MR modalities to predict outcome after perinatal asphyxia;
5) use MR patterns to develop better animal models to study pathophysiology of hypoxia-ischemia;
6) develop more advanced and safer imaging modalities for the developing nervous system that will enable the study of evolving damage with serial imaging of developing tracts;
7) use genetic strains of mice that are resistant and susceptible to injury and explore genomics and proteomics for novel genes and proteins that may shed light on possible probes for signaling pathways for protection;
8) develop appropriate therapies based on information gained from animal and human studies of the developmental profiles of injury and pathogenesis.
For information, please call 415-502-1099.
You may also want to read about the Brain Development Research Program.
Neurobiology Research Laboratory
Veterans Affairs Medical Center - Raymond Swanson, M.D.
Cell death in the CNS has several unique features stemming from the special characteristics of excitable cells. I have a longstanding interest in excitotoxic and oxidative neuronal death and in particular the role of astrocytes in this process. Ongoing studies in this area address functional differences between glutamate transporter subtypes, cysteine uptake by these transporters, and novel mechanisms of glutamate release from astrocytes. An important downstream effect of excitotoxic and oxidative stress is activation of PARP and PARG. PARP and PARG are enzymes which normally function in DNA repair, but which paradoxically mediate a critical intermediary step during excitotoxic and oxidative cell death. PARP activation is also an important mediator of microglial activation, and hence brain inflammation, by virtue of its interaction with NF-κB. A major aim of my research program is to elucidate the biochemical steps between activation of PARP and cell death under disease conditions in brain. Please email ray@itsa.ucsf.edu for information regarding post-doctoral research fellowship opportunities.
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Neuroimmunology Laboratory
Moffitt-Long Hospital - Stephen L. Hauser, M.D.
Our laboratory is focused in understanding the complex immunologic, genetic and environmental interactions that occur during autoimmune demyelination of the central nervous system (CNS). In multiple sclerosis (MS), symptoms are caused by immune mediated injury to the insulating myelin sheath within the CNS. A new model for MS in non-human primates was recently developed in our laboratory. The New World monkey common marmoset (Callithrix jacchus) develops a chronically relapsing form of autoimmune encephalitis with a pathological phenotype that closely resembles MS. Our data demonstrate that this model can be efficiently employed to characterize the role of the immune response in the pathologic processes that leads to demyelination and for the development of prospective therapies for MS (Science 274:2074-2057, 1996; J Immunology 158:1201-1207, 1997; J Molec Medicine 75:187-197, 1997). A second principal research goal of the laboratory is the identification and characterization of the major genetic factors that lead to MS susceptibility and pathogenesis. Our strategy for gene discovery relies on the screening of the entire genome in multiple-affected families. Systematic analysis of the inheritance of discrete chromosomal segments is used in an attempt to establish linkage between the disease phenotype and the chromosomal locations of the disease genes. The screen utilizes an extensive collection of microsatellites and other polymorphic markers, and applies modern statistical techniques as powerful tools to analyze segregation of disease in families. This strategy identified 19 susceptibility regions within small amounts of DNA sequence information, including the MHC region in chromosome 6p21 (Nature Genetics 13:469-471, 1996; Brain Pathology 6:289-322, 1996). The next step is to look for the disease-gene(s) in cloned segments of DNA covering such intervals. The identification and characterization of these genetic influences will play a major role in defining the basic etiology of MS and will influence therapeutics and prevention. For more informatin call 415-476-9211.
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Neurology Pain Clinical Research Center
UCSF/Mt. Zion Medical Center - Michael Rowbotham, M.D.
Understanding the mechanisms of neuropathic pain and improving therapy are the focus of research in the center. Mechanism based studies and clinical trials (single and multicenter) range in size from 20 to 150 subjects with neuropathic pain syndromes such as post-herpetic neuralgia, post-stroke pain, myelopathy, multiple sclerosis, trigeminal neuralgia, and peripheral neuropathy. Current studies include assessment of the role of cutaneous adrenergic receptors in post-herpetic pain, the efficacy and the sensory effects of acute and chronic opioid administration, and investigation of cutaneous mechanisms of post-herpetic pain by comparison of topical local anesthetics, NSAIDs and capsaicin. Articles: Lidocaine Patch: double-blind controlled study of a new treatment method for post-herpetic neuralgia. Pain 65:39-44, 1996. The relationship of pain, allodynia, and thermal sensation in post-herpetic neuralgia. Brain 119:347-354, 1996. For information call 415-885-7899.
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Neurology Pain Research Laboratory
Moffitt-Long Hospital - Howard Fields, M.D., Ph.D.,
Pain transmission is under the control of selective modulatory systems. These modulatory systems employ a variety of neurotransmitters including GABA, 5HT and endogenous opioid peptides. We use electrophysiological, pharmacological and anatomical approaches to answer such questions as: How is the pain signal controlled? What behavioral contexts activate pain suppressing or enhancing circuits? Where in these circuits do biogenic amine and peptide neurotransmitters act and how do they change the activity of neurons that either transmit or modulate the pain message? How do analgesic drugs act and what is the mechanism of tolerance to their action? Articles: A confocal laser microscopic study of enkephalin immunoreactive appositions onto physiologically identified neurons in the rostral ventromedial medulla. J Neuroscience 12:4023-4036, 1992. Serotonin immunoreactivity is contained in one physiological cell class in the rat rostral ventromedial medulla. J Neuroscience 14:1655-1665, 1994. For information call 415-476-4201.
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Neurorehabilitation Program
Moffitt-Long Hospital/San Francisco VAMC - Dr. Gary Abrams
The Neurorehabilitation program, directed by Dr. Gary Abrams, provides outpatient consultation services at weekly clinics at UCSF and the San Francisco VA Medical Center. The clinic works closely with the UCSF Neurocritical Care and Stroke Service and the UCSF Multiple Sclerosis Center. The Rehabilitation/Mobility Clinic at the VA Medical Center focuses on gait disorders and falls. Special resources of the program include a Neurological Fitness Unit that provides specialized exercise training for individuals with neurological disabilities under supervision of a neurologist and certified trainer. Programs offering novel methods of stroke and vestibular rehabilitation are offered in collaboration with the UCSF Department of Physical Therapy and Rehabilitation Sciences and the new UCSF Balance and Fall Center. Current research interests include effects of cortical electrical stimulation combined with rehabilitation therapy for stroke recovery, neural mechanisms of cognitive rehabilitation after stroke and traumatic brain injury using functional neuroimaging, and physical exercise in management of neurological disease.
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Neurocritical Care
Moffitt-Long Hospital and San Francisco General Hospital - Dr. Wade Smith, M.D., Ph.D.
The two year clinical fellowship provides clinical training and opportunities for clinical research in the area of neurocritical care and stroke. There is an emphasis on gaining expertise in critical care medicine and the specific applications to critical neurological disease. The program also includes an exposure to the broad spectrum of neurovascular disease. Current clinical efforts of the program are directed at acute stroke intervention including the use of neuroprotective agents, thrombolytics, and neurointerventional devices. Projects within the NeuroCritical Care Unit focus on developing techniques for the detection and monitoring of ischemia, with a focus on treatment of subarachnoid hemorrhage. For a complete bibliography, review of our program, and contact information, please go to http://www.ucsf.edu/stroke.
Vascular Neurology Fellowship Program
Moffitt-Long Hospital and San Francisco General Hospital - Dr. S. Claiborne Johnston, M.D., Ph.D.
The one to two year clinical fellowship provides clinical training and opportunities for clinical research in the area of stroke. Fellows will gain training satisfactory for board eligibility in vascular neurology. The two year fellowship combines a year of vascular neurology training with advanced training in clinical research, which can lead to a masters degree in clinical research. For more information go to http://www.ucsf.edu/stroke.
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Spine and Nerve Disease
Moffitt-Long Hospital - John W. Engstrom, M.D.
The clinical fellowship provides opportunities for development of expertise in evaluation and treatment of patients with neurologic complications of spine and peripheral nerve disease. Interdisciplinary conferences include spine radiology, neuromuscular, spine didactic conferences and EMG. Clinical research projects focus on development of optimal approaches to diagnosis and treatment. The fellow participates in the education of neurology residents. Articles: Back and Neck Pain. Harrison's Principles of Internal Medicine (16th ed.) Chapter 15, 2005. For more information, please call 415-476-1489 or write to John Engstrom.
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