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痴呆症（AD/ADRD），缺乏有效的治疗方法来控制这些破坏性疾病将导致老龄化社会的健康、经济和社会危机。在过去的几十年里，人们已经开展了一些研究来阐明 AD/ADRD 的分子基础，尽管潜在的机制仍然是个谜，但已经明确的是，α-突触核蛋白等几种蛋白质会造成膜损伤。 （α-syn）在疾病进展中发挥着关键作用，因此可能成为治疗干预的潜在目标，尽管我们付出了大量努力来剖析这些蛋白质-脂质相互作用的分子机制，但我们最近设计了能够控制它们的有效药物。一套基于纳米圆盘的荧光探针，可以可靠地报告 α-syn 对脂质双层的作用，基于这些成就，我们现在寻求进一步探索使用该工具包来发现调节剂，以改善膜结合和重塑活性。如果成功，所确定的候选物不仅可以作为研究 α-syn 生物学的有价值的试剂，而且可以作为 AD/ADRD 的潜在治疗方法。