New pharmacological tools to explore platelet GPR56 function

探索血小板 GPR56 功能的新药理学工具

• 批准号: 10408866
• 负责人: Alexander Vizurraga
• 金额: $ 3.08万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10408866
• 关键词: ADGR1 gene; Actins; Adhesions; Agonist; Anticoagulants; Benchmarking; Binding; Biochemical; Biological Assay; Biology; Blood; Blood Coagulation Disorders; Blood Platelets; Blood Vessels; Blood coagulation; Cells; Cessation of life; Chemicals; Coagulants; Coagulation Process; Collagen; Collagen Receptors; Companions; Coupled; Cytoskeleton; Data; Development; Dissociation; Event; Exhibits; Exposure to; Extracellular Domain; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; GTP-Binding Proteins; Goals; Hematological Disease; Hematology; Hemostatic function; Human; Impairment; In Vitro; Injury; Integrins; Investigation; Knowledge; Lead; Measures; Mediating; Modeling; Mus; Output; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Pharmacology; Pharmacology Study; Platelet Activation; Platelet Count measurement; Play; Property; Role; Shapes; Signal Transduction; Signaling Protein; Specificity; Stream; Surface; System; Testing; Thrombosis; Tissues; Transgenic Mice; Work; antagonist; base; chemical property; drug testing; force sensor; high throughput screening; human tissue; improved; in vivo; infancy; inhibitor; insight; member; novel; programs; receptor; response; small molecule; small molecule libraries; synthetic peptide; tool

Platelets are small cell fragments that circulate in the blood and their activation is critical for the blood clotting response. Initial platelet activation results from interactions with the collagen sub- layer that becomes exposed to the blood stream following blood vessel injury. Patients who have platelets with impaired receptiveness to collagen have severe bleeding disorders. Recently, we discovered that GPR56 (ADGRG1), a collagen-sensitive adhesion G protein-coupled receptor (AGPCR), is present on the surface of platelets and mediates their activation mechanism. AGPCRs are an understudied 33-member subfamily of GPCRs characterized in part by a bulky extracellular domain. Knowledge of how AGPCRs operate in vivo has stagnated due to a lack of available probe compounds. Consequently, I am finishing up large high throughput screens to identify novel small molecule activators and inhibitors of GPR56. Use of these compounds will expand our knowledge of both platelet biology and the AGPCR mechanism through my pharmacological investigation of GPR56 signaling in platelets. I propose two aims to advance knowledge of how GPR56 works in the platelet system: (1) Validate the new GPR56 activators and inhibitors found in my screens, and (2) utilize GPR56-specific compounds to assess how GPR56 mediates platelet signaling. Aim 1 will be accomplished using a battery of established cell-based and biochemical assays to measure GPR56 signaling. Aim 2 will examine the effects of GPR56 modulatory compounds in ex vivo human and mouse platelet assays. Blood clotting (thrombosis) is implicated in a large portion of deaths. My studies will not only provide critical insight into how blood clotting is regulated, but may also yield new classes of lead compounds that might be used to treat hematological diseases.

血小板是在血液中循环的小细胞碎片，其激活对于 血液凝结反应。初始血小板激活是由与胶原蛋白亚的相互作用引起的 血管损伤后会暴露于血流的层。患者有 接受胶原蛋白的血小板患有严重的出血性疾病。最近，我们 发现GPR56（ADGRG1），一种胶原蛋白的粘附G蛋白偶联受体 （AGPCR）存在于血小板的表面上，并介导了其激活机制。 AGPCR是一个研究的33个成员的GPCR的亚科，部分特征是笨重 细胞外域。了解AGPCR在体内如何操作的知识由于缺乏而停滞不前 可用的探针化合物。因此，我正在完成大型高通量屏幕 鉴定新型的小分子活化剂和GPR56的抑制剂。这些化合物的使用将 扩大我们对血小板生物学和AGPCR机制的了解 血小板中GPR56信号传导的药理研究。我提出了两个促进的目标 了解GPR56在血小板系统中的工作方式：（1）验证新的GPR56激活剂 以及在我的屏幕中发现的抑制剂，（2）利用GPR56特异性化合物来评估如何评估 GPR56介导血小板信号传导。 AIM 1将使用已建立的电池完成 基于细胞的和生化测定，以测量GPR56信号传导。 AIM 2将检查效果 在体内人和小鼠血小板测定中的GPR56调节化合物的。血液凝结 （血栓形成）与大部分死亡有关。我的学习不仅会提供关键 深入了解血液凝结的调节方式，但也可能产生新的铅化合物 这可能用于治疗血液学疾病。