ABCA7 dysfunction in Alzheimer's disease pathogenesis

ABCA7 功能障碍在阿尔茨海默病发病机制中的作用

• 批准号: 10212863
• 负责人: Amer Alam
• 金额: $ 43.58万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10212863
• 关键词: ATP binding cassette transporter 1; ATP phosphohydrolase; ATP-Binding Cassette Transporters; Accounting; Adenosine Triphosphate; Affect; Alzheimer' s Disease; Alzheimer' s disease therapeutic; Alzheimer' s disease therapy; Amyloid beta-Protein; Animals; Antibodies; Apolipoprotein A-I; Apolipoprotein E; Apolipoproteins; Apolipoproteins A; Area; Basic Science; Binding; Biochemical; Biological; Biological Assay; Biological Markers; Cause of Death; Cells; Cessation of life; Characteristics; Cholesterol; Collaborations; Complex; Cryoelectron Microscopy; Custom; Data; Dementia; Development; Diagnostic; Disease Progression; Environment; Foundations; Functional disorder; Future; Genetic Polymorphism; Healthcare; Homeostasis; Human; Hydrolysis; Immobilization; In Vitro; Knock-out; Late Onset Alzheimer Disease; Lecithin; Libraries; Light; Link; Lipid Bilayers; Lipids; Lipoproteins; Liposomes; Maintenance; Membrane; Molecular; Molecular Conformation; Nucleotides; Onset of illness; Pathogenesis; Pathway interactions; Phagocytosis; Physiological; Process; Production; Property; Protein Isoforms; Research; Resolution; Saposins; Scaffolding Protein; Single Nucleotide Polymorphism; Specificity; Spin Labels; Structure; Therapeutic; Time; Translational Research; Up-Regulation; Wild Type Mouse; Work; age related; base; clinical application; combat; drug discovery; genome wide association study; insight; member; metabolomics; mutant; nanobodies; nanodisk; nanoparticle; new therapeutic target; novel therapeutics; reconstitution; screening; small molecule; therapeutic target

Project Summary Alzheimer’s disease (AD) represents one of the foremost healthcare challenges of our times and is a leading cause of death worldwide. AD accounts for the overwhelming majority of dementias, which affect over 35 million people worldwide. This number is expected to double every twenty years. Dysfunction of the Adenosine triphosphate (ATP) Binding Cassette Subfamily A member 7 (ABCA7) transporter has been linked to both early and late onset AD through alterations in lipid homeostasis, Amyloid-Beta (Aβ) homeostasis, and phagocytosis. ABCA7 single nucleotide polymorphisms have been associated with late onset AD, suggesting that targeting ABCA7 could pave the way forward for new therapeutic AD strategies. The long-term objectives of this project are to gain mechanistic insight into human ABCA7 (hABCA7). We will use a combination of high-resolution structural analysis, in vitro functional characterization, and discovery of antibody and small molecule binders for hABCA7. The latter will aid in diagnostics and targeting, or function as potentiators and/or correctors of hABCA7 dysfunction. Specific Aim 1 deals the functional characterization of ABCA7 ATPase activity and the establishment of an in vitro transport assay to assay the lipid specificities and transport properties of the transporter and probe its interaction with different apolipoproteins. Specific Aim 2 deals with the detailed cryo- EM analysis of hABCA7 alone and in combination with nucleotides, different lipid environments, and small molecule and antibody based binders. Our results will shed light on the physiological functioning of human ABCA7, which is as of yet poorly understood, and validate its potential utilization as a therapeutic target for which future antibody and drug discovery efforts can be directed, thereby bridging basic and translational research for this relatively unexplored area of AD research.

项目摘要 阿尔茨海默病（AD）代表了我们这个时代最重要的医疗保健挑战之一， 全球范围内的死因。AD占痴呆症的绝大多数，影响超过3500万人 世界各地的人们。这个数字预计每20年翻一番。腺苷功能障碍 三磷酸（ATP）结合盒亚家族A成员7（ABCA 7）转运蛋白已与两种早期的细胞因子和细胞因子相关。 和迟发性AD通过脂质稳态、淀粉样蛋白-β（Aβ）稳态和吞噬作用的改变。 ABCA 7单核苷酸多态性与晚发性AD相关，这表明靶向 ABCA 7可以为新的治疗AD策略铺平道路。本项目的长期目标 是为了获得对人类ABCA 7（hABCA 7）的机制性洞察。我们将使用高分辨率的 结构分析、体外功能表征和抗体和小分子结合剂发现， hABCA 7。后者将有助于诊断和靶向，或作为hABCA 7的增效剂和/或校正剂发挥作用 功能障碍具体目标1涉及ABCA 7 ATP酶活性的功能表征和ABCA 7 ATP酶活性的功能表征。 建立体外转运试验，以测定脂质特异性和转运特性， 转运蛋白和探测其与不同载脂蛋白的相互作用。具体目标2涉及详细的冷冻- 单独的hABCA 7和与核苷酸组合的hABCA 7的EM分析，不同的脂质环境，和小的 分子和基于抗体的结合剂。我们的研究结果将揭示人类的生理功能， ABCA 7，这是迄今为止知之甚少，并验证其作为治疗靶点的潜在用途， 可以指导未来的抗体和药物发现工作，从而为基础研究和转化研究架起桥梁， 这是AD研究中相对未开发的领域。