This proposal represents investigators from the University of Southern California, Columbia University and State University of New York at Stony Brook Schools of Medicine who participate in a multi-disciplinary program on Cerebrovascular Mechanisms in the Aging Brain. The goal of the program is to advance current knowledge regarding the role of vasculature in the aging brain and major CNS disorders in elderly that predispose to cerebrovascular amyloidosis (e.g., Alzheimer's Disease and related amyloid-beta-peptide (Abeta) disorders, such as hereditary cerebral hemorrhage with amyloidosis Dutch type), Abeta-related vascular injury, brain damage and stroke. We will apply concepts and techniques developed in cerebrovascular biology, blood-brain barrier (BBB) and cerebrospinal fluid physiology, molecular biology, molecular genetics, transgene mice with age-dependent vascular risk factors, and tissues and cell cultures from patients diagnosed with AD. The program consists of five Research Projects and three Core resources. Project 1, Dr. Zlokovic will study the role of BBB and brain clearance in regulating Abeta concentrations in cerebral vessel wall and brain. Project the role of BBB and brain clearance in regulating Abeta concentrations in cerebral vessel wall and brain. Project 2, Dr. Van Nostrand will study Abeta production by cerebrovascular smooth muscle cells in relation to amyloidosis. Project, Dr. Stern will study the role of receptor for advanced glycation and end products in acute and chronic cerebrovascular perturbation caused by Abeta and stroke-risk factors. Project 44, Drs. Schreiber and Zlokovic will delineate the roles of Abeta dn amyloid in vascular hemostasis in relation to ischemic or hemorrhagic stroke. Project 5, Drs. Kalra and Rhodin will study the role of Abeta in migration of monocytes across the BBB and vascular wall. Core A is the administrative facility. Core B, Dr. Mackic and Kim will provide animal and cell culture facility. Core C, Dr. Miller will provide neuropathologic analysis. The integrated and complementary scientific research projects will provide a molecular and therapeutic rationale to prevent accumulation of Abeta and formation of amyloid in cerebral blood vessels and brain, and counteract age-dependent mechanisms responsible for abnormal vascular responses, injury and brain damage.
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