Biomedical Sciences Graduate Program | University of California, San Francisco

Douglas B. Gould, PhD
Genetic and molecular mechanisms of ocular and cerebrovascular diseases

Selected Publications | Complete Publications

phone	(415) 476-3592
email	GouldD@vision.ucsf.edu
additional websites
secondary research affiliation	Vascular & Cardiac Biology

The goal of my lab is to understand how mutations in the COL4A1 gene, and other basement membrane components, lead to multi-factorial human diseases. Understanding how mutations lead to disease, will lead to development of therapeutic interventions to prevent or treat these diseases. The COL4A1 protein is present in every tissue in the body. We have recently identified that mice with a Col4a1 mutation have pathology in multiple tissues including the lung, kidney, eye and brain. This work led to identification of COL4A1 mutations in human patients with a spectrum of cerebrovascular diseases including hemorrhagic stroke. Importantly, our experiments with the mouse model led to the hypothesis that Cesarean delivery of children with COL4A1 mutations could prevent death and life-long disability.

The objective is to continue to understand Col4a1 -related diseases with a focus on cerebrovascular and ocular diseases. One series of experiments will identify genetic modifier genes of Col4a1 -related diseases. In mice and in human patients, the diseases caused by a single mutation can look markedly different depending on the genetic context. We have already determined that a single dominant locus from one mouse strain can rescue severe eye developmental defects observed in a different strain. Identifying this gene, others like it, and how they rescue the disease will guide us to the kinds of therapies need to be developed for human patients with these diseases.

A second series of experiments will determine exactly which cell types are responsible for pathology. The approach is to use specific combinations of genetically altered mice to express mutant Col4a1 only in selected cell types. In this way, we can systematically test precisely which cell types lead to cerebrovascular and ocular diseases. The results are critical to understand which cell types will need to be targeted when considering therapeutic interventions.

COL4A1 mutations are an important cause of common and fatal human diseases. Our purpose is to use mouse genetic models, to determine where and how these mutations act. This information will be critical to determining how to prevent or treat disease in patients with COL4A1 mutations.

Selected Publications

Gould, D.B. , Phalan, F.C., van Mil, S.E., Sundberg, J.P., Massin, P., Vahedi, K., Huetink, P., Miner, J.H., Tournier-Lasserve, E., and John, S.W.M. (2006). COL4A1 mutation is associated with small vessel disease and predisposes to hemorrhagic stroke. N Engl J Med . 354 (14), 1489-96.
Highlighted in N Engl J Med. 354 (14), 1451-3

Breedveld, G.J., de Coo, I.F., Lequin, M.H., Arts, W.F.M., Heutink, P., Gould, D.B. , John, S.W.M., Oostra, B., and Mancini, G.M.S. (2006). Novel COL4A1 mutations in hereditary porencephaly: evidence for reduced penetrance. J Med Genet . 43 (6), 490-5.

Gould, D.B. , Phalan, F.C., Breedveld, G.J., van Mil, S.E., Smith, R.S., Schimenti, J.C., Aguglia, U., van der Knaap M.S., Heutink, P., and John, S.W.M. (2005). Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly. Science . 308 (5725), 1167-71.
Cited by Faculty of 1000. http://www.f1000biology.com/article/15905400/evaluation
Highlighted in Lancet Neurology - Vol. 4, Issue 7, July 2005, Page 400

Anderson, M.G., Libby, R.T., Gould, D.B. , Smith, R.S., and John, S.W.M. (2005). High-dose radiation treatment prevents neurodegeneration in glaucoma. Proc Natl Acad Sci USA . 102 (12), 4566-71.

Libby, R.T., Gould, D.B. , Anderson, M.G. and John, S.W.M. (2005). Complex genetics of glaucoma. Annu Rev Genomics Hum Genet . 6, 15-44.

Gould, D.B. , Miceli-Libby, L., Savinova, O.V., Torrado, M., Tomarev, S.I., Smith, R.S., and John, S.W.M. (2004). Genetically increasing Myoc expression supports a necessary pathologic role of abnormal proteins in glaucoma. Mol Cell Biol. 24 (20), 9019-25.

Gould, D.B. , Smith R.S., and John, S.W.M. (2004). Anterior segment development relevant to glaucoma. Int. J. Dev. Biol. 48 (8-9), 1015-29.

Gould, D.B. , Jaafar, M.S., Addison , M.K., Munier, F., Ritch, R., MacDonald, I.M., and Walter, M.A. (2004). Phenotypic and molecular characterization of seven patients with 6p25 deletion syndrome: Relevance to ocular dysgenesis and hearing impairment. BMC Med Genet. 5(1), 17 .

Gould, D.B. , and John, S.W.M. (2002). Anterior segment malformations and the developmental glaucomas are complex traits. Hum Mol Genet. 11 (10), 1185-93.

Kume T., Dengo, K.Y., Winfreyo, V., Gould, D.B. , Walter, M.A., and Hogan, B.L.M. (1998). The forkhead/winged helix Gene, Mf1, is disrupted in the pleiotropic mouse mutation, congnenital hydrocephalus. Cell. 93 (6), 985-96.

information last updated September 2006