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Endothelial dysfunction in the cerebral circulation

脑循环内皮功能障碍

基本信息

批准号：
8403744
负责人：
Zvonimir S Katusic
金额：
$ 42.99万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-01-01 至 2016-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8403744
关键词：
Address Agonist Alzheimer disease prevention Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid Amyloid beta-Protein Precursor Anabolism Arteries Biochemical Biochemical Process Biological Blood Circulation Blood Vessels Brain Cerebrovascular Circulation Cerebrovascular Disorders Cyclic GMP Data Development Disease Endothelial Cells Endothelium Enzymes Epidemiologic Studies Exercise Experimental Models Functional disorder Generations Genetic Goals Health Human Impaired cognition Impairment Incidence Knockout Mice Lead Link Modeling Modern Medicine Molecular Mus Neurodegenerative Disorders Neurologic Neurons Nitric Oxide Pathogenesis Pathology Pathway interactions Peptides Peroxisome Proliferation Physiological Play Prevention therapy Production Protein Isoforms Publishing Reporting Research Research Design Role Series Signal Transduction Signal Transduction Pathway Soluble Guanylate Cyclase Testing Therapeutic Tissues Up-Regulation Vascular Diseases amyloid pathology amyloid precursor protein processing base beta-site APP cleaving enzyme 1 cerebrovascular clinical practice defined contribution design human NOS3 protein in vivo interest lifestyle intervention mild cognitive impairment novel perpetrators prevent receptor receptor function research study secretase therapy design

项目摘要

ABSTRACT In the cerebral circulation, endothelial dysfunction caused by decreased biological activity and/or biosynthesis of nitric oxide (NO) is principal mechanism responsible for initiation and progression of vascular disease. Epidemiological studies established strong association between vascular disorders and incident Alzheimer's disease (AD). However, the molecular mechanisms linking cerebrovascular disease and AD are unknown. Our recently published findings (Circulation Research, 107:1498-1502, 2010) and preliminary experiments identified previously unrecognized role of endothelial NO in modulation of amyloid precursor protein (APP), ¿- secretase (BACE1) and amyloid-¿ peptide (A¿). Pharmacological or genetic inactivation of endothelial nitric oxide synthase (eNOS) causes up-regulation of APP and BACE1, leading to increased production of A¿. Moreover, we have preliminary evidence suggesting that activation of peroxisome proliferation-activated receptor-¿ (PPAR¿) exerts beneficial effect on endothelial function by enhancing production of NO. Moreover, activation of PPAR¿ prevents amyloidogenic processing of APP. Based on these finings we formulated following central hypothesis: impairment of endothelial function in the cerebral circulation plays a critical role in initiation and progression of AD pathology. To test this hypothesis we propose three specific aims: 1) Determine the molecular mechanisms that underline the effects of eNOS/cGMP signaling on expression and processing of APP, 2) Define the role of PPAR¿ in cerebrovascular endothelial function and processing of APP and 3) Assess the role of eNOS/cGMP signaling in initiation and progression of AD pathology. Cultured human brain microvascular endothelial cells will be used to study signal transduction pathways responsible for NO effects on generation of A¿. These studies will be followed by in vivo testing of the proposed hypothesis in genetically modified mice including eNOS, nNOS-, and iNOS-deficient mice, ¿1 or ¿1 isoform of soluble guanylate cyclase-deficient mice, and endothelial specific PPAR¿-defcient mice. To determine the role of eNOS in onset and progression of AD we propose to cross eNOS-deficient (eNOS-/-) mice with murine models of AD. Created AD mice lacking eNOS will provide new and unique models of AD relevant to study contribution of endothelial dysfunction to development of amyloid pathology. Functional, biochemical and morphological analyses will be preformed on microvessels and neuronal tissue. We anticipate that successful completion of the proposed studies will define the role of eNOS/cGMP signaling and activation of PPAR¿ in production of A¿. We expect the results of our proposed studies will establish cerebrovascular endothelium as a critical target in the prevention of AD thereby directing and concentrating therapeutic focus on the cerebral circulation.

摘要