Doug Gould
Dr. Gould obtained his B.Sc. with Specialization in Genetics and his Ph.D. in Medical Genetics from the University of Alberta in Edmonton, Canada. His PhD thesis, in the lab of Dr. Michael Walter, was to understand the molecular mechanisms that underlie ocular developmental defects. These defects that often lead to glaucoma in human families. In 2001, Dr. Gould moved to Dr. John’s lab. to undergo postdoctoral training.
Doug’s projects were primarily focused on using mouse models to understand the mechanisms of glaucoma. In the first of his two main projects, Doug sought to understand how mutations in the myocilin gene (Myoc) lead to primary open angle glaucoma (POAG). MYOC mutations are the most frequently identified genetic cause of POAG, but the pathogenic mechanism(s) remained elusive. Doug tested two contemporary hypotheses about MYOC pathogenesis by first characterizing a mouse model that over-expressed the MYOC protein and secondly by characterizing a mouse model that expressed a mutant Myoc allele that was analogous to a common and aggressive human mutation. Doug’s data indicate that abnormal protein molecules are necessary to induce disease and show that accumulation of these molecules in ocular cells is not sufficient to induce glaucoma. These data agree with a growing literature from other groups and a recent report suggesting that the abnormal mutant proteins have to be mis-targeted to the peroxisome to cause glaucoma.
Doug’s second major project was to develop new mouse models of glaucoma. A novel mutant mouse line was identified in a mutagenesis screen. Doug mapped the gene and identified a mutation in the type IV collagen alpha 1 gene (Col4a1). He showed that Col4a1 mutation can cause ocular dysgenesis in a genetic context dependent manner. On a permissive background mutant mice have severe anterior segment dysgenesis and optic nerve hypoplasia. On a resistant background both phenotypes are profoundly modified and we have identified a genetic modifier locus that is able to rescue anterior segment dysgenesis.
While identifying the gene and characterizing the ocular phenotypes, we discovered that Col4a1 mutant mice also had cerebrovascular defects including large cerebral cavities and multi-focal cerebral hemorrhages. This work led to the identification of COL4A1 mutations as a major genetic cause of a rare but severe human disease called porencephaly and the speculation that alleles of COL4A1 may contribute more broadly to hemorrhagic stroke in human patients. Importantly, Doug’s experiments show that Col4a1 mutations weaken blood vessels and predispose to trauma-induced hemorrhage in mice. Important collaborations demonstrated that this is also true in some human families. This work suggests that behavioral modifications/interventions may substantially decrease the risk of severe (even lethal) hemorrhage that can be induced by trauma in individuals with these mutations at all stages of life.
Dr. Gould started his own laboratory in 2006 at UCSF School of Medicine in the Departments of Ophthalmology and Anatomy and the Institute for Human Genetics where he is continuing to study the mechanisms of Col4a1-realted pathogenesis in the eye and other organs. gouldd@vision.ucsf.edu.
Gould DB, Marchant JK, Savinova OV, Smith RS, John SWM. 2007. Col4a1 mutation causes endoplasmic reticulum stress and genetically modifiable ocular dysgenesis. Hum Mol Genet http://hmg.oxfordjournals.org/cgi/reprint/ddm024v1
Gould DB, Reedy M, Wilson LA, Smith RS, Johnson RL, John SWM. 2006. Mutant myocilin non-secretion in vivo is not sufficient to cause glaucoma. Mol Cell Biol 26: 8427-8436
Gould DB, Phalan FC, van Mil SE, Sundberg JP, Vahedi K, Massin P, Germaine Bousser M, Heutink P, Miner JH, Tournier-Lasserve E, John SWM. 2006. Role of COL4A1 in small-vessel disease and hemorrhagic stroke. N E J Med 354: 1489-1496
Breedveld G, de Coo RF, Lequin MH, Arts WF, Heutink P, Gould DB, John SWM, Oostra B, Mancini GM. 2005. Novel mutations in three families confirm a major role of COL4A1 in hereditary porencephaly. J Med Genet 43: 490-495
Gould DB, Phalan FC, Breedveld GJ, van Mil SE, Smith RS, Schimenti JC, Aguglia U, van der Knaap MS, Heutink P, John SWM. 2005. Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly. Science 308: 1167-1171
Anderson MG, Libby RT, Gould DB, Smith RS, John SWM. 2005. High-dose radiation with bone marrow transfer prevents neurodegeneration in an inherited glaucoma. Proc Natl Acad Sci USA 102: 4566-4571 http://www.pnas.org/cgi/content/full/102/12/4566
Gould DB, Miceli-Libby L, Savinova OV, Torrado M, Tomarev SI, Smith RS, John SWM. 2004. Genetically increasing Myoc expression supports a necessary pathologic role of abnormal proteins in glaucoma. Mol Cell Biol 24:9019-9025
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