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: 10360428
• 负责人: Alexander Vizurraga
• 金额: $ 3.8万
• 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/10360428
• 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; base; chemical property; drug testing; force sensor; high throughput screening; human tissue; improved; in vivo; infancy; inhibitor/antagonist; 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，它们的激活对于血液循环至关重要。 凝血反应最初的血小板活化是由于与胶原亚基的相互作用， 血管损伤后暴露于血流的层。的患者 具有受损的胶原受体的血小板具有严重的出血障碍。最近我们 发现GPR56（ADGRG1），一种胶原敏感的粘附G蛋白偶联受体， （AGPCR）存在于血小板表面并介导其活化机制。 AGPCR是GPCR的一个未充分研究的33个成员的亚家族，其特征部分在于庞大的 胞外区关于AGPCR如何在体内运作的知识由于缺乏 可用的探针化合物。因此，我正在完成大型高通量屏幕， 鉴定新小分子GPR56激活剂和抑制剂。这些化合物的使用将 扩大我们的知识，血小板生物学和AGPCR机制，通过我的 血小板中GPR56信号传导的药理学研究。我提出两个目标， GPR56在血小板系统中的作用：（1）研究新的GPR56激活剂 和抑制剂在我的屏幕上发现，（2）利用GPR56特异性化合物来评估如何 GPR56介导血小板信号传导。目标1将通过一系列已建立的 基于细胞的和生物化学测定来测量GPR56信号传导。目标2将检验 GPR56调节化合物在离体人和小鼠血小板测定中的浓度。血液凝固 （血栓形成）与大部分死亡有关。我的研究不仅能提供 深入了解血液凝固是如何调节的，但也可能产生新的先导化合物 可以用来治疗血液病