Endothelial dysfunction in the cerebral circulation

脑循环内皮功能障碍

基本信息

批准号：
8216679
负责人：
Zvonimir S Katusic
金额：
$ 46.58万
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/8216679
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 neurocognitive impairment novel perpetrators prevent receptor receptor function research study secretase therapy design

项目摘要

DESCRIPTION (provided by applicant): 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), 2- secretase (BACE1) and amyloid-2 peptide (A2). Pharmacological or genetic inactivation of endothelial nitric oxide synthase (eNOS) causes up-regulation of APP and BACE1, leading to increased production of A2. Moreover, we have preliminary evidence suggesting that activation of peroxisome proliferation-activated receptor-4 (PPAR4) exerts beneficial effect on endothelial function by enhancing production of NO. Moreover, activation of PPAR4 prevents amyloidogenic processing of APP. Based on these findings 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 PPAR4 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 A2. These studies will be followed by in vivo testing of the proposed hypothesis in genetically modified mice including eNOS, nNOS-, and iNOS-deficient mice, 11 or 21 isoform of soluble guanylate cyclase-deficient mice, and endothelial specific PPAR4-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 performed 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 PPAR4 in production of A2. 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. PUBLIC HEALTH RELEVANCE: Dysfunction of endothelial cells (inner lining of the brain arteries) is believed to play an important role in initiation and progression of Alzheimer's disease. The long-term goal of the studies proposed in this application is to determine the mechanisms underlying alterations in function of brain blood vessels that could contribute to development of Alzheimer's disease. We propose to create new experimental models of Alzheimer's disease which will be very useful in studies designed to determine contribution of diseased arteries to development of the cognitive impairment. In addition, these models will be employed in testing novel therapies for prevention and treatment of Alzheimer's disease.

描述（由申请人提供）：在脑循环中，由一氧化氮（NO）生物活性和/或生物合成降低引起的内皮功能障碍是导致血管疾病发生和进展的主要机制。流行病学研究证实血管疾病与阿尔茨海默病 (AD) 之间存在密切关联。然而，脑血管疾病和 AD 之间的分子机制尚不清楚。我们最近发表的研究结果 (Circulation Research, 107:1498-1502, 2010) 和初步实验确定了内皮 NO 在淀粉样前体蛋白 (APP)、2-分泌酶 (BACE1) 和淀粉样蛋白 2 肽 (A2) 调节中的先前未被认识的作用。内皮一氧化氮合酶 (eNOS) 的药理学或基因失活会导致 APP 和 BACE1 上调，从而导致 A2 产量增加。此外，我们有初步证据表明，过氧化物酶体增殖激活受体 4 (PPAR4) 的激活通过增强 NO 的产生对内皮功能产生有益的影响。此外，PPAR4 的激活可阻止 APP 的淀粉样蛋白形成过程。基于这些发现，我们制定了以下中心假设：脑循环中内皮功能的损伤在 AD 病理的发生和进展中起着关键作用。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 APP 表达和加工影响的分子机制，2) 确定 PPAR4 在脑血管内皮功能和 APP 加工中的作用，3)评估 eNOS/cGMP 信号传导在 AD 病理的发生和进展中的作用。培养的人脑微血管内皮细胞将用于研究 NO 对 A2 生成影响的信号转导途径。这些研究之后将在转基因小鼠中对所提出的假设进行体内测试，这些小鼠包括 eNOS、nNOS 和 iNOS 缺陷小鼠、11 或 21 亚型可溶性鸟苷酸环化酶缺陷小鼠以及内皮特异性 PPAR4 缺陷小鼠。为了确定 eNOS 在 AD 发病和进展中的作用，我们建议将 eNOS 缺陷 (eNOS-/-) 小鼠与 AD 小鼠模型进行杂交。缺乏 eNOS 的 AD 小鼠将提供新的、独特的 AD 模型，用于研究内皮功能障碍对淀粉样蛋白病理学发展的贡献。将对微血管和神经元组织进行功能、生化和形态学分析。我们预计拟议研究的成功完成将明确 eNOS/cGMP 信号传导和 PPAR4 激活在 A2 生产中的作用。我们预计我们提出的研究结果将把脑血管内皮确立为预防 AD 的关键靶点，从而将治疗重点集中在脑循环上。公共卫生相关性：内皮细胞（脑动脉内层）功能障碍被认为在阿尔茨海默病的发生和进展中发挥着重要作用。本申请中提出的研究的长期目标是确定可能导致阿尔茨海默病发展的脑血管功能改变的潜在机制。我们建议创建新的阿尔茨海默病实验模型，这对于旨在确定患病动脉对认知障碍发展的影响的研究非常有用。此外，这些模型将用于测试预防和治疗阿尔茨海默病的新疗法。