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.

项目概要 阿尔茨海默病 (AD) 是当今时代最重要的医疗保健挑战之一，也是一种领先的疾病 AD 是全世界死亡的主要原因，痴呆症影响了超过 3500 万人。 腺苷功能障碍的人数预计每二十年就会增加一倍。 三磷酸 (ATP) 结合盒亚家族 A 成员 7 (ABCA7) 转运蛋白已与早期 以及通过脂质稳态、β-淀粉样蛋白 (Aβ) 稳态和吞噬作用的改变而导致迟发性 AD。 ABCA7 单核苷酸多态性与迟发性 AD 相关，表明靶向 ABCA7 可以为新的 AD 治疗策略铺平道路 该项目的长期目标。 我们将使用高分辨率的组合来深入了解人类 ABCA7 (hABCA7)。 结构分析、体外功能表征以及抗体和小分子结合物的发现 hABCA7。后者将有助于诊断和靶向，或作为 hABCA7 的增强剂和/或校正剂。 具体目标 1 涉及 ABCA7 ATP 酶活性的功能特征和 建立体外转运测定，以测定脂质测定的特异性和转运特性 转运蛋白并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- hABCA7 单独以及与核苷酸、不同脂质环境和小分子组合的电镜分析 我们的结果将揭示人类的生理功能。 ABCA7 至今仍知之甚少，并验证了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研究中相对未被探索的领域。