This multi-PI project will provide integrated expertise in stroke and Alzheimer's disease to address a cerebrovascular disorder of wide prevalence. Careful neuropathological analyses indicate that cerebral microscopic hemorrhage is an extremely common feature of the aging brain. The current project proposal focuses on these hemorrhagic changes in a comprehensive way, with a goal to define the anatomic and pathophysiological substrate of cerebral microscopic hemorrhage as well as develop therapeutic strategies that can be incorporated clinically in efforts directed to reduce consequences of cerebral microscopic hemorrhage. This RO1 was initiated in 1984 and work from this project has demonstrated that the brain has unique hemostatic regulatory capacities, a phenomenon termed """"""""brain-specific hemostasis regulation."""""""" More recently, we have developed the concept of """"""""mixed cerebrovascular disease"""""""" to address the increasingly recognized clinical conundrum of patients presenting with ischemic stroke symptoms coexisting with hemorrhagic phenomena that are largely subclinical. The current application may therefore be conceptualized as combining these two novel concepts, ie, how brain specific hemostasis regulation mediates and modulates mixed cerebrovascular disease.
Our specific aims are as follows:
Specific Aim 1 : To demonstrate exacerbation, mitigation, and mechanisms of brain microvascular hemorrhage in vivo, using models of cerebral amyloid angiopathy and aging.
Specific Aim 2 : To demonstrate microvascular integrity-altering mechanisms of in vitro endothelial injury mediated by cerebral amyloid angiopathy and aging.
Specific Aim 3 : To demonstrate the relationships between human brain microhemorrhage, vascular risk factors, blood-brain barrier characteristics, and cognitive function. Completion of these studies will point the way toward protection and maintenance of brain microvessel integrity against the challenges of aging and vascular risks. These issues affect virtually the entire population of individuals over the course of the usual lif expectancy. The studies incorporate a transgenic animal model that develops cerebral amyloid angiopathy and microhemorrhages, cell culture studies, and analysis of human brain autopsy samples;the latter emphasizes the clinical relevance of these studies. Part of the novelty of the project is the genuine collaborative multi-PI effort that combines expertise in stroke and Alzheimer's disease, contributing to the high translational significance.

Public Health Relevance

This project will analyze development of small areas of bleeding in aging brain. Animal models, cell cultures, and human brain autopsy specimens will be studied. The project will address how these small areas of bleeding develop in the aging brain, what are the clinical consequences, and how they can be mitigated.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS020989-26
Application #
8534287
Study Section
Acute Neural Injury and Epilepsy Study Section (ANIE)
Program Officer
Koenig, James I
Project Start
1984-07-01
Project End
2017-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
26
Fiscal Year
2013
Total Cost
$526,076
Indirect Cost
$184,653
Name
University of California Irvine
Department
Neurology
Type
Schools of Medicine
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Fisher, Mark; Kapur, Kevin; Soo, Sylvia et al. (2018) Disseminated Microinfarctions with Cerebral Microbleeds. J Stroke Cerebrovasc Dis 27:e95-e97
Sumbria, Rachita K; Grigoryan, Mher Mahoney; Vasilevko, Vitaly et al. (2018) Aging exacerbates development of cerebral microbleeds in a mouse model. J Neuroinflammation 15:69
Chang, Rudy; Castillo, Juan; Zambon, Alexander C et al. (2018) Brain Endothelial Erythrophagocytosis and Hemoglobin Transmigration Across Brain Endothelium: Implications for Pathogenesis of Cerebral Microbleeds. Front Cell Neurosci 12:279
Hainsworth, Atticus H; Fisher, Mark J (2017) A dysfunctional blood-brain barrier and cerebral small vessel disease. Neurology 88:420-421
Sumbria, Rachita K; Vasilevko, Vitaly; Grigoryan, Mher Mahoney et al. (2017) Effects of phosphodiesterase 3A modulation on murine cerebral microhemorrhages. J Neuroinflammation 14:114
Lo, Patrick; Crouzet, Christian; Vasilevko, Vitaly et al. (2016) Corrigendum to ""Visualization of microbleeds with optical histology in mouse model of cerebral amyloid angiopathy"" [105, May 2016, 109-113]. Microvasc Res 106:137
Lo, Patrick; Crouzet, Christian; Vasilevko, Vitaly et al. (2016) Visualization of microbleeds with optical histology in mouse model of cerebral amyloid angiopathy. Microvasc Res 105:109-13
Passos, Giselle F; Kilday, Kelley; Gillen, Daniel L et al. (2016) Experimental hypertension increases spontaneous intracerebral hemorrhages in a mouse model of cerebral amyloidosis. J Cereb Blood Flow Metab 36:399-404
Sumbria, Rachita K; Grigoryan, Mher Mahoney; Vasilevko, Vitaly et al. (2016) A murine model of inflammation-induced cerebral microbleeds. J Neuroinflammation 13:218
Fisher, Mark; Moores, Lisa; Alsharif, Mohamad N et al. (2016) Definition and Implications of the Preventable Stroke. JAMA Neurol 73:186-9

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