Vascular malformations of the brain are a rare but important cause of stroke. Clinically, an important subtype is brain arteriovenous malformation (AVM). As-yet unknown defects in angiogenesis and vascular assembly are thought to undergird development of the clinical phenotype. Understanding the signaling which results in proper CNS vascular development and integrity is the likeliest approach to developing relevant therapies to prevent hemorrhage in these conditions. A unifying theme of this proposal is a vertically integrated program that can relate clinical observations to various aspects of the underlying genetic and cell-to-cell signaling abnormalities. Project 1 (Young) is a clinical investigation that will identify novel candidate genetic variants associated with AVM susceptibility using genome-wide association methods, therefore encompassing project-related signaling pathways. Project 2 (Hashimoto) addresses macrovascular remodeling due to matrix metalloprotease (MMP) activity and inflammatory activity. Project 3 (Boudreau) concerns homeobox genes, which are master regulatory mechanisms in the regulation of extracellular matrix and angiogenesis;this project focuses on the anti-angiogenic properties of HOX A5, which we have found to be deficient in human BAVM tissue. Project 4 (Nishimura) investigates the role of astrocyte-endothelial cell interactions in a key signaling pathway for cerebrovascular homeostasis- integrin-mediated control of TGF-?;TGF-? signaling is implicated in the only known heritable form of AVM, i.e., hereditary hemorrhagic telangectasias. The three cores serve all projects. The Administrative Core A (Young) coordinates PPG activities. The Data Management Core B (McCulloch) serves as the central mechanism for clinical data collection, organized data input and analyses. The Laboratory Core C (Su) furnishes a central laboratory resource for models used in the laboratory project including murine vascular dysplasia, flow loading of large arteries, and human-to-rodent tissue transplant;and serves as a central human surgical specimen tissue bank. At the present time, AVM treatment is extirpative and entails relatively high costs with significant risks. Improved mechanistic insight into the pathophysiology of the disease will facilitate development of novel therapies and biomarkers for a disease that currently has no specific medical therapy. This program represents a unique coupling of clinical and basic investigators, along with a unique, large clinical database and tissue bank, to address a complex and important clinical problem.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS044155-09
Application #
8243603
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Fountain, Jane W
Project Start
2002-07-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
9
Fiscal Year
2012
Total Cost
$1,239,211
Indirect Cost
$477,836
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
Kremer, P H C; Koeleman, B P C; Pawlikowska, L et al. (2015) Evaluation of genetic risk loci for intracranial aneurysms in sporadic arteriovenous malformations of the brain. J Neurol Neurosurg Psychiatry 86:524-9
Choi, Eun-Jung; Chen, Wanqiu; Jun, Kristine et al. (2014) Novel brain arteriovenous malformation mouse models for type 1 hereditary hemorrhagic telangiectasia. PLoS One 9:e88511
Han, Zhenying; Shen, Fanxia; He, Yue et al. (2014) Activation of ?-7 nicotinic acetylcholine receptor reduces ischemic stroke injury through reduction of pro-inflammatory macrophages and oxidative stress. PLoS One 9:e105711
Wada, Kosuke; Makino, Hiroshi; Shimada, Kenji et al. (2014) Translational research using a mouse model of intracranial aneurysm. Transl Stroke Res 5:248-51
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
Chen, Wanqiu; Young, William L; Su, Hua (2014) Induction of brain arteriovenous malformation in the adult mouse. Methods Mol Biol 1135:309-16
Rutledge, W Caleb; Ko, Nerissa U; Lawton, Michael T et al. (2014) Hemorrhage rates and risk factors in the natural history course of brain arteriovenous malformations. Transl Stroke Res 5:538-42
Takayanagi, Takehiko; Crawford, Kevin J; Kobayashi, Tomonori et al. (2014) Caveolin 1 is critical for abdominal aortic aneurysm formation induced by angiotensin II and inhibition of lysyl oxidase. Clin Sci (Lond) 126:785-94
Tada, Yoshiteru; Wada, Kosuke; Shimada, Kenji et al. (2014) Roles of hypertension in the rupture of intracranial aneurysms. Stroke 45:579-86
Sallach, Jessica; Di Pasquale, Giovanni; Larcher, Fernando et al. (2014) Tropism-modified AAV vectors overcome barriers to successful cutaneous therapy. Mol Ther 22:929-39

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