Intracerebral hemorrhages (ICH) and hemorrhagic stroke are a particularly fatal form of stroke and an important cause of long-term disability. This is especially true when they affect children and young adults. Effective treatments for hemorrhagic stroke are limited, and so ICH prevention is paramount for reducing the impact of this debilitating condition. However, preventative therapies often require an understanding of the pathogenic mechanism underlying ICH. Genetic studies have successfully defined the etiologies of some forms of ICH, however there is still a tremendous unmet need in determining the underlying causes of most forms of CVD. We have discovered that mutations in type IV collagen alpha 1 (COL4A1) cause a broad spectrum of highly penetrant cerebrovascular diseases (CVDs), including peri-natal stroke, congenital porencephaly, leukoencephalopathy, cerebral microbleeds, intracranial aneurysm, and ICH. In addition to multiple reports of COL4A1 mutations causing dominantly inherited CVD, our recent data suggest that 5-10% of patients suffering from sporadic ICHs have mutations in COL4A1 or its paralog COL4A2. Thus, according to American Heart Association estimates, mutations in COL4A1 and COL4A2 could cause up to 12,000 new cases of spontaneous ICH in the United States each year and 300,000 cases worldwide. Here we use novel genetic models of CVD to identify distinct roles for COL4A1 in vascular development and maintenance. Using genetic, molecular, and biochemical approaches we will directly test the regulation by COL4A1 of fundamental cell- signaling pathways that are critical for normal vascular development. Finally, we will use novel pre-clinical models of human CVD that we have generated to identify therapeutics that may be developed for use in patients and that may reduce their risk of suffering debilitating or fatal ICHs.

Public Health Relevance

Stroke is common and devastating disease and a leading cause of death and long-term disability. This research proposal seeks to characterize the molecular and cellular mechanisms by which mutations in the gene coding for COL4A1, a basement membrane protein, lead to cerebrovascular disease. A better understanding of the underlying pathogenic mechanisms may lead to the development of targeted therapeutic strategies to prevent stroke.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
1R01NS083830-01A1
Application #
8762215
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Koenig, James I
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
City
San Francisco
State
CA
Country
United States
Zip Code
94143