Stroke is the fourth leading cause of mortality and a major cause of morbidity in the United States. Despite significant progress in the prevention and treatment of ischemic stroke, less is known about mechanisms and prevention of hemorrhagic stroke. We will use a hereditary stroke syndrome, Cerebral Cavernous Malformation (CCM), to study mechanisms underlying hemorrhagic stroke and cerebrovascular disease. CCM is characterized by chronic vascular leak leading to inflammation and by subsequent acute bleeding resulting in hemorrhagic stroke. This study will have direct and immediate application to the more than 100,000 veterans estimated to have CCM, and has significant potential to affect millions of veteran as our conclusions are applied more broadly to cerebrovascular disease. A significant subset of CCM cases is familial and represents a genetic cause for hemorrhagic stroke. Three separate genes have been identified in these families associated with CCM (KRIT1, OSM and PDCD10). These widely expressed genes are required in the endothelium for normal vascular development, endothelial cell cytoskeletal structure, and endothelial barrier function. In particular, the loss f KRIT1 and OSM results in very similar phenotypes in embryos, adult mice, and endothelial cell culture. Both KRIT1 and OSM have been found to bind each other as part of a complex of cytoplasmic proteins involved in scaffolding small GTPases involved in the cellular response to stress and controlling the cellular cytoskeleton and barrier function. A major endothelial signaling cascade involves nitric oxide (NO) produced by an endothelial isoform of nitric oxide synthase (eNOS) to induce smooth muscle relaxation, prevent platelet aggregation, limit smooth muscle proliferation, and inhibit leucocyte adhesion. The loss of KRIT1 in fibroblasts results in increased reactive oxygen species (ROS). However, whether increased ROS plays a role in the pathogenesis of CCM due to mutations in KRIT1, OSM, or PDCD10 has not been established. Importantly, some evidence suggests that the dysregulated signaling pathways associated with loss of function of each CCM gene may be different. Therefore, we hypothesize that increased ROS as a result of the loss of CCM proteins is a key contributor to vascular pathology in CCM, which can be rescued by scavenging excess superoxide, and serves as the downstream common pathogenic mechanism of CCM disease. This work will test an important functional hypothesis and clarify a promising potential therapeutic target in a hemorrhagic stroke syndrome and has the potential to provide a roadmap for bench-to-bedside translation to human clinical trials in the near future. Further, this work may serve as the foundation for future examinations of the use of superoxide scavengers in the treatment and prevention of other cerebrovascular disease. This proposal has both immediate translational potential for more than 100,000 veterans estimated to have CCM disease, and will underlie additional progress for diseases more broadly affecting the Veterans population.

Public Health Relevance

Stroke is the fourth leading cause of death in America and a leading cause of adult disability. Despite research and new therapies for the prevention and treatment of ischemic stroke, there has been little advancement in the prevention of hemorrhagic stroke. Here we will study a monogenic hemorrhagic stroke syndrome; Cerebral Cavernous Malformation (CCM). This syndrome has been increasingly recognized with the advent of MRI for diagnosis and is well represented in the Veteran population. Multiple studies confirm that CCM is found in 1 of every 200 persons, indicating that this disease potentially affects more than 100,000 Veterans. Our studies will employ cell culture, signaling, as well as ex vivo and in vivo systems to understand the mechanism of CCM and to develop new treatments for CCM and other forms of hemorrhagic stroke. The insights developed by this study will have direct application to more common ailments in the Veteran population including hemorrhagic stroke, ischemia-reperfusion injury, and other vascular diseases.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX002976-02
Application #
9206095
Study Section
Cardiovascular Studies B (CARB)
Project Start
2015-10-01
Project End
2019-09-30
Budget Start
2016-10-01
Budget End
2017-09-30
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
VA Salt Lake City Healthcare System
Department
Type
Independent Hospitals
DUNS #
009094756
City
Salt Lake City
State
UT
Country
United States
Zip Code
84148