PHARMACOLOGICAL MODULATION OF PIEZO1 CHANNELS

Piezo1 通道的药理学调节

基本信息

批准号：
10659738
负责人：
YUN LUO
金额：
$ 37.32万
依托单位：
WESTERN UNIVERSITY OF HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-05 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10659738
关键词：
Acceleration Affinity Agonist Arthrogryposis Basic Science Binding Binding Sites Biological Biological Assay Calcium Cartilage injury Chemicals Clinic Clinical Complex Computing Methodologies Degenerative polyarthritis Disease Docking Dose Electrophysiology (science)Elements Erythrocytes Eukaryotic Cell Extracellular Domain Free Energy Homologous Gene Human Hydrophobicity Hypertension Image Infection prevention Inflammation Ion Channel Lead Libraries Ligand Binding Lymphedema Machine Learning Malaria Maps Measurement Mechanics Membrane Proteins Methods Modeling Molecular Molecular Conformation Muscle Cells Mutagenesis Natural regeneration Outcome Pain Pancreatitis Pathway Analysis Pathway interactions Peer Review Physical Exercise Physical Performance Physiological Piezo 1 ion channel Piezo 2 ion channel Piezo ion channels Play Printing Property Pruritus Publishing Rapid screening Research Resolution Role Stimulus Structure Structure-Activity Relationship System Testing Time Transmembrane Domain Vertebrates Writing analog base bone repair design drug candidate improved inhibitor innovation interdisciplinary approach lymphatic vessel mechanical force mechanotransduction molecular dynamics novel pathogen pharmacologic pharmacophore prevent rational design response reverse genetics scaffold screening small molecule tumor growth tumor progression virtual virtual screening

项目摘要

Summary Mechanosensitive Piezo ion channels enable eukaryotic cells to sense mechanical forces. In vertebrates, two Piezo homologs, Piezo1 and Piezo2, play central roles in all major physiological systems and are associated with numerous diseases including hypertension, xerocytosis, lymphedema, arthrogryposis, inflammation, pain, and cancer progression. Hence, pharmacological modulation of specific Piezo homologs could help treat many human ailments. Yet, this effort is currently limited by the paucity of homolog-selective pharmacological agents and the lack of a clear molecular understanding by which Piezo channels open and close their pore in response to physical and chemical stimuli. To bridge this gap, this proposal will leverage a recently identified pharmacological binding site in mammalian Piezo1 channels. Specifically, we will use reverse genetics, high-resolution electrophysiology, and calcium imaging to dissect structural pathways by which the binding of the small molecule Yoda1 energetically promotes an open state (Aim 1). In parallel, we will deploy an innovative, multi-pronged approach combining binding free energy calculations, structure-activity relationships, machine learning-based virtual screening of ultra- large billion-compounds library, and rapid experimental screening assays to identify novel molecules that preferentially bind conducting or non-conducting channel conformations, thus potentially acting as Piezo1 activators and inhibitors, respectively (Aim 2). Successful completion of this project will identify discrete mechanotrasnduction pathways associated with pharmacological activation of Piezo1 channels and identify novel pharmacological activators and inhibitors of Piezo1 channels with potential research and clinical value.

概括机械敏感压电离子通道使真核细胞能够感知机械力。在在脊椎动物中，两个 Piezo 同源物 Piezo1 和 Piezo2 在所有主要生理功能中发挥着核心作用系统并与许多疾病相关，包括高血压、干细胞增多症、淋巴水肿、关节弯曲、炎症、疼痛和癌症进展。因此，药理调节特定的压电同系物可以帮助治疗许多人类疾病。然而，这种努力是目前由于同系物选择性药物的缺乏以及缺乏清晰的分子理解压电通道打开和关闭其孔以响应物理和化学刺激。为了弥补这一差距，该提案将利用最近确定的哺乳动物 Piezo1 通道中的药理学结合位点。具体来说，我们将使用反向遗传学、高分辨率电生理学和钙成像来剖析结构通路小分子 Yoda1 的结合大力促进开放状态（目标 1）。与此同时，我们将部署一种创新的、多管齐下的方法，结合结合自由能计算、结构-活性关系、基于机器学习的超庞大的十亿化合物库，以及快速的实验筛选分析来识别新的优先结合导电或非导电通道构象的分子，因此分别可能充当 Piezo1 激活剂和抑制剂（目标 2）。顺利完成该项目将确定与相关的离散机械传导途径 Piezo1 通道的药理激活并鉴定新型药理激活剂和具有潜在研究和临床价值的Piezo1通道抑制剂。