CELL AND MOLECULAR PATHOBIOLGY OF ALZHEIMER'S DISEASE

阿尔茨海默病的细胞和分子病理学

• 批准号: 8534648
• 负责人: RALPH A. NIXON
• 金额: $ 186.73万
• 依托单位: NATHAN S. KLINE INSTITUTE FOR PSYCH RES
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-15 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8534648
• 关键词: Accounting; Address; Advisory Committees; Alzheimer' s Disease; Alzheimer' s disease risk; Animal Model; Area; Autophagocytosis; Autopsy; Binding Proteins; Biological; Biology; Cell Survival; Cell model; Cells; Cholesterol; Communication; Complement; Consultations; Data; Disease; Drug Targeting; Early Endosome; Education; Endocytosis; Exocytosis; Failure; Fertilization; Fostering; Functional disorder; Funding; Future; Genes; Genetic; Human; Human Resources; Image; Impairment; Individual; International; Investigation; Late Onset Alzheimer Disease; Lead; Link; Lipids; Lysosomes; Manuscripts; Mediating; Mentors; Methodology; Molecular; Monitor; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Neurosciences; Neurotic Disorders; Neurotics; New York; Outcome; Pathogenesis; Pathology; Pathway interactions; Patients; Play; Population; Positioning Attribute; Presenile Alzheimer Dementia; Process; Productivity; Progress Reports; Proteins; Proteolysis; Publications; Publishing; Quality Control; Recruitment Activity; Regulation; Research; Research Personnel; Resources; Risk Factors; Role; Series; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Staging; Stress; System; Teleconferences; Testing; Therapeutic; Toxic effect; Training Programs; Training and Education; Transgenic Mice; Validation; Video Microscopy; Work; age related; base; biological systems; deprivation; effective therapy; innovation; innovative technologies; insight; interdisciplinary approach; late endosome; meetings; mouse model; multidisciplinary; neuroimaging; neurotrophic factor; novel; novel strategies; overexpression; post gamma-globulins; presenilin; presenilin-1; programs; remediation; research study; response; retrograde transport; voltage

DESCRIPTION (provided by applicant) In the past PPG term, we have unequivocally linked the genes causing early onset Alzheimer's disease (AD) directly to functions' within endocytic and autophagic pathways of the lysosomal system, documenting specific impairment of these functions beginning at the earliest stages of AD. We propose to validate further our novel conceptual framework that positions the lysosomal system as a common primary target for disruption by diverse genetic and environmental AD-risk factors. Preliminary data support the working hypothesis that cumulative "hits" to multiple sites within the endocytic and autophagy pathways in AD cause selective failures of vesicular retrograde transport and signaling, impaired clearance of pathogenic proteins including AP, neurotic dystrophy, and neurodegeneration. The four Projects apply a tightly integrated multidisciplinary approach to study the highly dynamic interplay among lysosome pathway compartments. Individual Projects focus mainly on distinct facets of the entire lysosomal system - the biological and genetic regulation of early endosome signaling (Projects 1, 4 respectively), late endosome/exosome biology (Project 3), and autophagy/lysosome function (Project 2) - thus enabling us to define comprehensively how specific major AD-risk factors disrupt the lysosomal system with significant pathogenic consequences. Innovative technologies from single-neuron gene profiling to video microscopy and high voltage immunogold EM imaging will be applied to patient cells and our novel mouse models. In addition to defining the mechanisms underlying pathobiology induced by key AD-risk factors (APP, cholesterol, presenilin, cystatin C, neurotrophin deprivation), we will provide the rationale and validation for innovative therapeutic approaches to AD, including modulators of endocytosis and lipid-mediated AD pathologies (Project 1), autophagy/lysosomal remediation (Project 2), exosome-based modulation and cystatin C-based therapies (Project 3), and drug target identification within APP/neurotrophin signaling pathways promoting neuron survival (Project 4). Validation for one or more of these new approaches will have significant impact on realizing therapeutics for AD and other major aging-related neurodegenerative diseases.

描述（由申请人提供）在过去的PPG期限中，我们明确地将导致阿尔茨海默氏病早期发病（AD）的基因直接连接到溶酶体系统的内吞和自噬途径内的功能，记录了这些功能的特定功能，这些功能始于AD的最早阶段。我们建议进一步验证我们的新颖概念框架，该概念框架将溶酶体系统定位为通过各种遗传和环境广告风险因素破坏的常见主要目标。初步数据支持以下假设，即AD中累积的“命中”到内吞和自噬途径内的多个位点会导致囊泡逆行转运和信号传导的选择性故障，对病原蛋白的清除受损，包括AP，神经性神经性营养不良症和神经化学因素。这四个项目采用紧密整合的多学科方法来研究溶酶体途径隔室之间高度动态的相互作用。个别项目主要集中在整个溶酶体系统的不同面上 - 早期内体信号传导的生物学和遗传调节（分别项目1、4），晚期内体/外泌体生物学（项目3）以及自噬/溶酶体功能（项目2） - 从而使我们能够全面地定义了对大型AD -rys lysom cake cancention cacky cackention cakention cancement actection cancemove cancement actecom的重要性很大。从单神经元基因分析到视频显微镜和高压免疫质量EM成像的创新技术将应用于患者细胞和我们的新型小鼠模型。除了定义由关键广告风险因素引起的病理生物学的基本机制（APP，胆固醇，老年蛋白，囊蛋白C，神经营养蛋白剥夺）外，我们还将为AD的创新治疗方法提供理由和验证，包括内部和Lipid-siped Adecied Adivied Adiviention-project Adivientiand-project Adivient（Project Adivient）（Project Adived-Sivientiand-project）（Project of Project）（项目） 2），基于外部的调节和基于胱抑素C的疗法（项目3）以及在APP/Neurotrophin信号传导途径中促进神经元存活的途径（项目4）。对一种或多种新方法的验证将对实现AD和其他与衰老有关的神经退行性疾病的治疗剂产生重大影响。