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，它们的激活对 凝血反应。最初的血小板激活是由与胶原亚单位相互作用的结果 血管损伤后暴露在血流中的一层。曾患过 对胶原蛋白的接受性受损的血小板有严重的出血障碍。最近，我们 发现胶原敏感的黏附G蛋白偶联受体GPR56(ADGRG1) (AGPCR)，存在于血小板表面，调节其激活机制。 AGPCR是一个未被研究的GPCR亚家族，有33个成员，部分特征是 胞外域。由于缺乏对AGPCRs在体内如何运作的了解，已陷入停滞 可用的探测化合物。因此，我正在完成大型高吞吐量屏幕，以 鉴定新的GPR56小分子激活剂和抑制剂。使用这些化合物将 通过My My扩展我们对血小板生物学和AGPCR机制的了解 血小板GPR56信号通路的药理学研究我提出了两个目标来推进 了解GPR56如何在血小板系统中发挥作用：(1)验证新的GPR56激活剂 和在我屏幕上发现的抑制剂，以及(2)利用GPR56特定的化合物来评估 GPR56介导血小板信号转导。目标1将使用一系列已建立的 以细胞为基础的和生化分析来测量GPR56信号。目标2将检查这些影响 GPR56调节化合物在体外人和小鼠血小板检测中的应用。凝血 (血栓形成)与很大一部分死亡有关。我的研究不仅将提供关键的 洞察血液凝结是如何调节的，但也可能产生新类别的铅化合物 可能被用来治疗血液病。