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Douglas B. Gould, PhD

Douglas B. Gould, PhD
Associate Professor, Departments of Ophthalmology and Anatomy
Institute for Human Genetics
Research Summary:
Genetic Dissection of Extracellular Matrix in Development and Disease
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

Jeanne M, Jorgensen J, Gould D.B. (2015). Molecular and Genetic Analyses of Collagen Type IV Mutant Mouse Models of Spontaneous Intracerebral Hemorrhage Identify Mechanisms for Stroke Prevention. Circulation 131 (18), 1555-65.

Ghosh R, Wang L, Wang ES, Perera BG, Igbaria A, Morita S, Prado K, Thamsen M, Caswell D, Macias H, Weiberth KF, Gliedt MJ, Alavi MV, Hari SB, Mitra AK, Bhhatarai B, Schürer SC, Snapp EL, Gould D.B., German MS, Backes BJ, Maly DJ, Oakes SA, Papa FR. (2014). Allosteric inhibition of the IRE1α RNase preserves cell viability and function during endoplasmic reticulum stress. Cell 158 (3), 534-48.

Kuo DS, Labelle-Dumais C, Mao M, Jeanne M, Kauffman WB, Allen J, Favor J, Gould D.B. (2014). Allelic heterogeneity contributes to variability in ocular dysgenesis, myopathy and brain malformations caused by Col4a1 and Col4a2 mutations. Human Mol Genet. 23 (7), 1709-22.

Kuo, D.S., Labelle–Dumais, C., Gould, D.B. (2012). COL4A1 and COL4A2 mutations and disease: insights into pathogenic mechanisms and potential therapeutic targets. Hum Mol Genet. 12 (R1), R97–110.

Weng, Y–C., Sonni, A., Labelle–Dumais, C., de Leau, M., Kauffman, W.B., Jeanne, M., Biffi, A., Greenberg, S.M., Rosand, J., Gould, D.B. (2012). COL4A1 mutations in patients with sporadic, late­–onset intracerebral hemorrhage. Ann Neurol. 71 (4), 470–7.

Jeanne, M., Labelle–Dumais, C., Jorgensen J., Kauffman W.B., Mancini, G.M., Favor, J., Valant, V., Greenberg, S.M., Rosand, J., Gould, D.B. (2012). COL4A2 mutations impair COL4A1 and COL4A2 secretion and cause hemorrhagic stroke. Am J Hum Genet. 90 (1), 91–101.

Verbeek, E., Verheijen, F.W., Meuwissen, M.E.C., Govaert, P., Licht, D.J., Kuo, D.S., Poulton, C.J., Schot, R., Luquin, M.H., Dudink, J., Halley, D.J., de Coo, R.I.F., den Hollander, J., Oegema, R., Gould, D.B., Mancini, G.M.S. (2012). COL4A2 mutation associated with familial porencephaly and small–vessel disease. Eur J Hum Genet. Epub doi:10.1038/ejhg.2012.20.

Labelle-Dumais, C., Dilworth, D.J., Harrington, E.P., de Leau, M., Lyons, D., Kabaeva, Z., Manzini, M.C., Dobyns W.B., Walsh, C.A., Michele, D. E., and Gould, D. B. (2011).  Col4a1 mutation causes ocular dysgenesis, neuronal localization defects and myopathy and models Walker–Warburg Syndrome. PLoS Genet 7 (5), e1002062.

Bai, X., Dilworth D.J., Weng, Y.C., and Gould, D.B. (2009).  Developmental distribution of collagen IV isoforms and relevance to ocular diseases. Matrix Biol. 28 (4), 194-201.

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

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.
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.