Brain arteriovenous malformations (AVMs) are an important cause of intracranial hemorrhage (ICH) in young adults. The etiology and pathogenesis of AVMs are not well understood. Treatment is invasive and controversy remains over the clinical management of unruptured AVMs. Previous work by our group has identified genes associated with AVM and new ICH in the clinical course. However, the determinants of new ICH may differ from those that influence poor outcome from a hemorrhagic event or treatment-related injury. Identification of genetic predictors of functional outcome after brain injury may help facilitate risk prediction for better management of AVM patients and advance understanding of hemorrhagic diseases of the brain. The overall goal of this research proposal is to better understand the pathogenesis of brain AVMs and the underlying genetic susceptibility to adverse outcomes. Specifically, my goals are to identify genetic predictors of outcome measured by the modified Rankin scale after 1) brain injury from ICH or 2) invasive treatment in brain AVM patients, using a candidate gene approach. Thirdly, we will address methodological issues of population stratification, i.e., genetic confounding by race/ethnicity, which is a potential problem for all genetic association studies conducted in multiethnic populations. These objectives will be completed in a carefully characterized, actively followed cohort of existing and new AVM cases from the UCSF Brain AVM Study Project and healthy controls. The candidate is a PhD trained cardiovascular genetic epidemiologist dedicated to a career in patient-oriented stroke research focusing on hemorrhagic diseases of the brain. This application proposes a comprehensive 5-year plan to develop the candidate into an independent stroke researcher, including clinical training, such as attendance in stroke clinics and operating room to observe stroke patient treatment, advanced training in statistical methods and bioinformatics, and hands on laboratory training in high throughput genotyping techniques. The candidate's long-term objective is to become an independent leader in stroke genetics research by combining skills in epidemiology, biostatistics, genetics, and neurology. The Mentored Patient-Oriented Career Development Award and the advanced training milieu at UCSF will ensure the candidate's success in these endeavors.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23NS058357-05
Application #
8290058
Study Section
NST-2 Subcommittee (NST)
Program Officer
Moy, Claudia S
Project Start
2008-07-01
Project End
2013-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
5
Fiscal Year
2012
Total Cost
$187,380
Indirect Cost
$13,880
Name
University of California San Francisco
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Bendjilali, Nasrine; Nelson, Jeffrey; Weinsheimer, Shantel et al. (2014) Common variants on 9p21.3 are associated with brain arteriovenous malformations with accompanying arterial aneurysms. J Neurol Neurosurg Psychiatry 85:1280-3
Kim, Helen; Al-Shahi Salman, Rustam; McCulloch, Charles E et al. (2014) Untreated brain arteriovenous malformation: patient-level meta-analysis of hemorrhage predictors. Neurology 83:590-7
Bendjilali, Nasrine; Kim, Helen; Weinsheimer, Shantel et al. (2013) A genome-wide investigation of copy number variation in patients with sporadic brain arteriovenous malformation. PLoS One 8:e71434
Guo, Yi; Saunders, Tara; Su, Hua et al. (2012) Silent intralesional microhemorrhage as a risk factor for brain arteriovenous malformation rupture. Stroke 43:1240-6
Mikhak, Bahar; Weinsheimer, Shantel; Pawlikowska, Ludmila et al. (2011) Angiopoietin-like 4 (ANGPTL4) gene polymorphisms and risk of brain arteriovenous malformations. Cerebrovasc Dis 31:338-45
Weinsheimer, Shantel M; Xu, Huichun; Achrol, Achal S et al. (2011) Gene expression profiling of blood in brain arteriovenous malformation patients. Transl Stroke Res 2:575-87
Kim, Helen; Su, Hua; Weinsheimer, Shantel et al. (2011) Brain arteriovenous malformation pathogenesis: a response-to-injury paradigm. Acta Neurochir Suppl 111:83-92
Gabriel, Rodney A; Kim, Helen; Sidney, Stephen et al. (2010) Ten-year detection rate of brain arteriovenous malformations in a large, multiethnic, defined population. Stroke 41:21-6
Kim, Helen; McCulloch, Charles E; Johnston, S Claiborne et al. (2010) Comparison of 2 approaches for determining the natural history risk of brain arteriovenous malformation rupture. Am J Epidemiol 171:1317-22
Lawton, Michael T; Kim, Helen; McCulloch, Charles E et al. (2010) A supplementary grading scale for selecting patients with brain arteriovenous malformations for surgery. Neurosurgery 66:702-13; discussion 713

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