Douglas B. Gould, PhD

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.