Most common human diseases are complex. Environmental factors are superimposed upon genetic predispositions to determine the presence or absence and severity of disease. We recently identified that mice with mutations in the type IV collagen alpha 1 gene (Col4a1) are predisposed to cerebral hemorrhage (Science 308 (5725), 1167-71 and N Engl J Med. 354 (14), 1489-96). Hemorrhagic stroke is a leading cause of death and the leading cause of long-term disability. We have since identified COL4A1 mutations in human patients with a spectrum of cerebrovascular diseases ranging from porencephaly to cerebral white matter abnormalities.

COL4A1 is the major component of basement membranes. Mutations have pleiotropic effects that are dependent on genetic context. Detailed analysis of Col4a1 mutant mice revealed hallmarks of age-related macular degeneration (AMD) including spontaneous choroidal neo-vascularization. AMD is already the leading cause of blindness in the elderly and the prevalence is expected to increase. Despite this, the precise disease mechanisms and location of insult remain unknown. Mouse models of AMD have been difficult to establish reflecting the complexity of the human disease. Col4a1 mutant mice represent a unique and valuable resource for understanding the pathogenic mechanisms of this common and complex blinding disease.

The major goals of my research program are to understand the cellular processes that lead from COL4A1 mutations (and other basement membrane components) to human diseases. I am using multiple approaches to dissect genetic interactions and to test mechanistic hypotheses. Understanding basic disease mechanisms could help people with COL4A1 mutations, and potentially others, reduce the risk of stroke and retain their vision into old age.