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.

抽象的在脑循环中，生物学活性和/或生物合成降低引起的内皮功能障碍一氧化氮（NO）是负责血管疾病的主动性和进展的主要机制。流行病学研究建立了血管疾病与阿尔茨海默氏症事件之间的密切关联疾病（AD）。但是，连接脑血管疾病和AD的分子机制尚不清楚。我们的最近发表的发现（循环研究，107：1498-1502，2010）和初步实验在调节淀粉样前体蛋白（APP）的调节中，鉴定出先前无法识别的作用，泌尿酶（BACE1）和淀粉样蛋白肽（a。）。内皮氮的药理或遗传失活氧化物合酶（ENOS）引起APP和BACE1的上调，从而导致a的产生增加。此外，我们有初步证据表明过氧化物体增殖激活激活接收器 - （PPAR¿）通过增强NO的产生对内皮功能产生有益的作用。而且， PPAR的激活可防止APP的淀粉样蛋白生成处理。根据这些罚款，我们制定了遵循中心假设：脑循环中内皮功能的损害起着关键在AD病理学的启动和进展中的作用。为了检验这一假设，我们提出了三个具体目标： 1）确定强调eNOS/CGMP信号传导对表达和表达和 APP的处理，2）定义PPAR在脑血管内皮功能和APP处理中的作用 3）评估eNOS/CGMP信号传导在AD病理学的启动和进展中的作用。养殖的人脑微血管内皮细胞将用于研究负责NO的信号转导途径对a的产生的影响。这些研究将随后在体内对所提出的假设进行体内测试一般修饰的小鼠，包括eNOS，NNOS-和iNOS缺陷小鼠，1或»1或1同工型可溶性鸟苷酸环化酶缺陷小鼠和内皮特异性PPAR® -Defcient小鼠。确定 AD的发作和进展中的eNOS我们建议将缺陷eNOS（eNOS - / - ）与鼠模型交叉广告。创建的AD小鼠缺乏eNOS将提供与研究贡献有关的新的独特广告模型淀粉样病理发展的内皮功能障碍。功能性，生化和形态学分析将在微血管和神经元组织上进行预报。我们预计成功完成拟议的研究将定义eNOS/CGMP信号传导和PPAR激活在A a生产中的作用。我们预计我们提出的研究的结果将建立脑血管原始疗法作为关键目标预防AD，从而指导和集中治疗专注于脑循环。