Brain Microvascular Determinants of Alzheimers Disease

阿尔茨海默病的脑微血管决定因素

• 批准号: 8129775
• 负责人: JOHN Calvert RUTLEDGE
• 金额: $ 42.11万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-15 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8129775
• 关键词: Affect; Age; Alzheimer' s Disease; Apoptosis; Astrocytes; Atherosclerosis; Attenuated; Binding; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain Injuries; Cell Adhesion Molecules; Cell Culture Techniques; Clinical; Dementia; Development; Disease; Electron Spin Resonance Spectroscopy; Endothelial Cells; Endothelium; Fatty Acids; Future; Gender; Generations; Goals; Human; Inflammatory; Ingestion; Injury; Interdisciplinary Study; Investigation; JUN gene; Lipids; Lipolysis; Measures; Mediating; Methods; Microvascular Permeability; Modeling; Molecular Conformation; Morbidity - disease rate; Mus; Neuronal Injury; Neurons; Pathogenesis; Pathology; Pathway interactions; Permeability; Phosphotransferases; Play; Positioning Attribute; Reactive Oxygen Species; Research Project Grants; Rodent; Saturated Fatty Acids; Signal Pathway; Site; Small Interfering RNA; Spin Labels; TLR4 gene; TNF gene; Testing; Tissues; Toll-like receptors; Translational Research; Tumor Necrosis Factor-alpha; Very low density lipoprotein; Work; activating transcription factor 3; apolipoprotein E-3; apolipoprotein E-4; cell injury; cytokine; design; fluidity; injured; innovation; lipid mediator; lipoprotein lipase; mitogen-activated protein kinase p38; mortality; neuropathology; neurovascular unit; particle; prevent; public health relevance; research study; response; saturated fat; stress activated protein kinase; translational approach; volunteer

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most common form of dementia and an important cause of morbidity and mortality in the U.S. AD and the complications of atherosclerotic cardiovascular disease (ASCVD) are strongly associated suggesting common, but unknown, pathogenetic factors. Our proposal will focus on the investigation of the interactions of very low-density lipoprotein (VLDL) lipolysis products with apolipoprotein (apo) E3 and apoE4, brain microvascular endothelial cells and astrocytes, and blood-brain barrier (BBB) permeability. Brain microvascular endothelial cells and astrocytes are important components of the brain neurovascular unit, which governs BBB permeability, and play key roles in the neuropathology of AD. The overall goal of this proposal is to understand the mechanisms of the microvascular contribution to the pathogenesis of AD. This project is an integrated, translational research project that will: (1) Investigate the effects of very low-density lipoprotein (VLDL) lipolysis products on apoE4 conformation and brain microvascular injury and BBB permeability, (2) Examine intracellular signaling pathways by which VLDL lipolysis products injure human microvascular endothelial cells and increase BBB permeability, and (3) Determine the mechanisms by which VLDL lipolysis products injure astrocytes and induce apoptosis. We expect that injury of the neurovascular unit by apoE4 and VLDL lipolysis products could initiate and/or perpetuate AD. We are well positioned to perform these studies because we have an established interdisciplinary research group to complete the aims of the proposal. These proposed studies are innovative and will advance the field by: (1) Providing a better understanding of the vascular determinates of AD, (2) Using an integrated, translational approach to comprehensively investigate a relevant and important clinical problem, Alzheimer's disease, (3) Using new and more sensitive biophysical approaches to examine mechanisms of disease development, (4) Using brain microvascular endothelial cells and astrocytes from AD volunteers, providing more relevant results, (5) Developing a comprehensive new method to measure rodent BBB permeability, and (6) Providing rationales for future therapies for Alzheimer's disease. PUBLIC HEALTH RELEVANCE: Alzheimer's disease is an increasingly important cause of morbidity and mortality in the U.S. Recent work has indicated that there is a strong component of microvascular pathology that contributes to Alzheimer's disease. The overall goal of this proposal is to define mechanisms contributing to the development of Alzheimer's disease and design potential therapies to prevent the onset of this devastating condition.

描述（由申请人提供）：阿尔茨海默氏病（AD）是痴呆症的最常见形式，也是美国AD中发病率和死亡率的重要原因，而动脉粥样硬化心血管疾病（ASCVD）的并发症是密切相关的，暗示了常见，但未知的病原因素。我们的建议将集中于对非常低密度脂蛋白（VLDL）脂肪解析产品与载脂蛋白（APO）E3和APOE4，脑微血管内皮细胞和星形胶质细胞以及血脑屏障（BBB）的相互作用的研究。脑微血管内皮细胞和星形胶质细胞是脑神经血管单元的重要组成部分，它控制BBB渗透性，并在AD神经病理学中起关键作用。该提案的总体目标是了解微血管对AD发病机理的贡献的机制。 This project is an integrated, translational research project that will: (1) Investigate the effects of very low-density lipoprotein (VLDL) lipolysis products on apoE4 conformation and brain microvascular injury and BBB permeability, (2) Examine intracellular signaling pathways by which VLDL lipolysis products injure human microvascular endothelial cells and increase BBB permeability, and (3) Determine the mechanisms by which VLDL脂解产品会损害星形胶质细胞并诱导凋亡。我们预计APOE4和VLDL脂肪分解产品对神经血管单位的损伤可能启动和/或永久化AD。我们有能力进行这些研究，因为我们有一个既定的跨学科研究小组来完成该提案的目标。这些拟议的研究具有创新性，将通过以下方面的发展，通过以下方式提高领域的发展，对AD的血管确定，（2）使用综合的，翻译的方法全面研究相关且重要的临床问题，Alzheimer病，（3）使用新的和更敏感的生物物理学方法，使用疾病的机制（4），（3）使用新的和更敏感的生物物理学方法（4）（4）志愿者提供了更相关的结果，（5）开发一种综合的新方法来测量啮齿动物BBB的通透性，（6）为阿尔茨海默氏病的未来疗法提供理由。 公共卫生相关性：在美国，阿尔茨海默氏病是发病率和死亡率越来越重要的原因，最近的工作表明，微血管病理的很大一部分会导致阿尔茨海默氏病。该提案的总体目的是定义有助于发展阿尔茨海默氏病和设计潜在疗法以防止这种毁灭性疾病发作的机制。