Endothelial dysfunction in the cerebral circulation

脑循环内皮功能障碍

• 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
• 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' s Disease; Alzheimer' 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

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 在脑循环中，由于生物活性和/或生物合成降低而引起的内皮功能障碍 一氧化氮（NO）的释放是引起血管疾病发生和发展的主要机制。 流行病学研究证实血管疾病与阿尔茨海默病之间存在密切联系 疾病（AD）。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 确定了以前未被认识到的内皮NO在淀粉样前体蛋白（APP）调节中的作用， 分泌酶（BACE 1）和淀粉样肽（A）。内皮一氧化氮的药理学或遗传学失活 一氧化氮合酶（eNOS）引起APP和BACE 1的上调，导致A？的产生增加。 此外，我们有初步证据表明，激活过氧化物酶体增殖激活 过氧化物酶体增殖物激活受体（PPAR）通过增加NO的产生对内皮功能产生有益的作用。此外， 激活的过氧化物酶体增殖物激活体阻止淀粉样蛋白的加工。 以下中心假设：脑循环中内皮功能的损害在脑血管疾病中起关键作用。 在AD病理学的起始和进展中的作用。为了验证这一假设，我们提出了三个具体目标： 1)确定强调eNOS/cGMP信号传导对表达的影响的分子机制， 2）明确PPAR在脑血管内皮功能和APP加工中的作用 3）评估eNOS/cGMP信号在AD病理发生和发展中的作用。培养的人 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世代的影响这些研究之后，将在体内测试提出的假设， 转基因小鼠，包括eNOS、nNOS-和iNOS-缺陷小鼠，可溶性NOS的<$1或<$1亚型， 鸟苷酸环化酶缺陷小鼠和内皮特异性过氧化物酶体增殖物激活受体缺陷小鼠。确定的作用 eNOS在AD发病和进展中的作用我们建议将eNOS缺陷（eNOS-/-）小鼠与小鼠模型交叉 的AD。缺乏eNOS的AD小鼠将提供与研究贡献相关的新的独特的AD模型 内皮功能障碍与淀粉样病变的关系。功能、生化和形态 将对微血管和神经元组织进行分析。我们预计， 这项研究将确定eNOS/cGMP信号传导和激活PPAR <$在A <$产生中的作用。 我们希望我们所提出的研究结果将建立脑血管内皮细胞作为一个关键的目标， 预防AD，从而将治疗重点集中在脑循环上。