A cost-effective, high-throughput screening platform for modulator discovery of a-synuclein membrane interactions involved in neurodegenerative diseases

一种经济有效的高通量筛选平台，用于发现神经退行性疾病中涉及的α-突触核蛋白膜相互作用的调节剂

• 批准号: 10667047
• 负责人: Huan Bao
• 金额: $ 28.98万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-15 至 2023-11-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10667047
• 关键词: Abbreviations; Acceleration; Achievement; Aging; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease therapeutic; Amyloid; Antibodies; Binding; Biochemical; Biological Assay; Biology; Cells; Clinical Trials; Color; Consumption; DNA; Defect; Disease; Disease Progression; Dyes; Economics; Eligibility Determination; Engineering; Engraftment; Financial Hardship; Flow Cytometry; Fluorescence; Fluorescent Probes; Health; Libraries; Lipid Bilayers; Lipids; Membrane; Methods; Microscopy; Molecular; Neurodegenerative Disorders; Parkinson Disease; Persons; Pharmaceutical Preparations; Play; Protein Array; Proteins; Public Health; Reagent; Reporting; Role; Scaffolding Protein; Societies; Sodium Chloride; Sorting; Source; Specificity; Surface Plasmon Resonance; Therapeutic; Therapeutic Intervention; Time; Yeasts; alpha synuclein; amyloid peptide; antibody libraries; candidate identification; cost effective; disorder control; drug discovery; effective therapy; efficacy evaluation; high throughput screening; inhibitor; interest; monomer; mutant; nanobodies; nanodisk; protein misfolding; rational design; reconstitution; screening; sensor; small molecule libraries; social; targeted treatment; therapeutic development; therapeutic target

Millions of people are afflicted with Alzheimer's Disease and Alzheimer's Disease Related Dementias (AD/ADRD) every year. The lack of effective treatments to control these devastating diseases will result in a health, economic and social crisis in an aging society. Thus, numerous studies have been carried out to elucidate the molecular basis of AD/ADRD in the past few decades. Although the underlying mechanism remains enigmatic, it is well established that membrane damage by several proteins such as α-synuclein (α-syn) plays a critical role in disease progression and thus could be a potential target for therapeutic interventions. Despite extensive efforts to dissect the molecular mechanism of these protein-lipid interactions, effective drugs that can control them are scarce. We recently engineered a suite of nanodisc-based fluorescent probes that can robustly report the action of α-syn on the lipid bilayer. Building on these achievements, we now seek to further explore the use of this toolkit for modulator discovery to ameliorate membrane binding and remodeling activities of α-syn aggregates. If successful, the identified candidates will not only serve as valuable reagents to study the biology of α-syn, but also as potential therapeutics for AD/ADRD.

每年有数百万人患有阿尔茨海默病和阿尔茨海默病相关性痴呆（AD/ADRD）。缺乏有效的治疗方法来控制这些毁灭性的疾病将导致老龄化社会的健康，经济和社会危机。因此，在过去的几十年里，已经进行了大量的研究来阐明AD/ADRD的分子基础。尽管潜在的机制仍然是个谜，但已经确定的是，几种蛋白质（如α-突触核蛋白（α-syn））造成的膜损伤在疾病进展中起着关键作用，因此可能是治疗干预的潜在靶点。尽管广泛的努力来剖析这些蛋白质-脂质相互作用的分子机制，但可以控制它们的有效药物很少。我们最近设计了一套基于纳米盘的荧光探针，可以可靠地报告α-syn对脂质双层的作用。在这些成就的基础上，我们现在寻求进一步探索使用该工具包进行调节剂发现，以改善α-syn聚集体的膜结合和重塑活性。如果成功，所鉴定的候选物将不仅作为研究α-syn生物学的有价值的试剂，而且作为AD/ADRD的潜在治疗剂。