Endothelial Dysfunction In The Cerebral Circulation

脑循环中的内皮功能障碍

• 批准号: 8787484
• 负责人: Zvonimir S Katusic
• 金额: $ 45.09万
• 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 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8787484
• 关键词: Address; Agonist; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease model; 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; 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 peptide; amyloid precursor protein processing; base; beta-site APP cleaving enzyme 1; cerebrovascular; clinical practice; cognitive development; defined contribution; design; endothelial dysfunction; genetic approach; human NOS3 protein; in vivo; interest; lifestyle intervention; mild cognitive impairment; novel; peptide A; 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/或生物合成减少而引起的内皮功能障碍 一氧化氮(NO)是血管疾病发生和发展的主要机制。 流行病学研究证实了血管疾病与阿尔茨海默病发病之间的密切联系 疾病(AD)。然而，脑血管疾病与阿尔茨海默病之间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 内皮型一氧化氮在淀粉样前体蛋白(APP)调节中的作用 分泌酶(BACE1)和淀粉样多肽(A？)。内皮细胞一氧化氮的药理学或遗传失活 一氧化氮合酶(ENOS)引起APP和BACE1的上调，导致A？的产生增加。 此外，我们有初步证据表明，过氧化物酶体的激活--增殖激活 受体(PPAR)通过促进NO的产生，对血管内皮细胞功能起到有利的作用。此外， PPAR的激活阻止了APP的淀粉样变性处理。基于这些结果，我们制定了 遵循中心假说：脑循环中内皮功能的损害起着关键作用 在AD病理的发生和发展中的作用。为了验证这一假设，我们提出了三个具体目标： 1)确定eNOS/cGMP信号转导途径影响eNOS/cGMP基因表达的分子机制 APP的加工，2)明确PPAR在脑血管内皮功能中的作用和APP的加工 3)探讨eNOS/cGMP信号在AD病理发生发展中的作用。修养的人 脑微血管内皮细胞将被用于研究NO的信号转导途径 对A？世代的影响。在这些研究之后，将在体内测试所提出的假设 转基因小鼠，包括eNOS、nNOS-和iNOS缺陷小鼠，1或1亚型可溶性 鸟苷环化酶缺陷小鼠和内皮特异性PPAR缺陷小鼠。确定…的角色 内皮型一氧化氮合酶在阿尔茨海默病发生发展中的作用我们建议将内皮型一氧化氮合酶缺陷(eNOS-/-)小鼠与小鼠模型杂交 公元一代的。建立的缺乏eNOS的AD小鼠将提供与研究贡献相关的新的、独特的AD模型 血管内皮细胞功能障碍与淀粉样变病理的关系。功能、生化和形态 将对微血管和神经元组织进行分析。我们期待着成功完成 拟议的研究将确定eNOS/cGMP信号转导和激活PPAR？在A？产生中的作用。 我们期望我们提出的研究结果将使脑血管内皮细胞成为 预防阿尔茨海默病，从而将治疗重点集中在脑循环上。