Endogenous suppression of integrin signaling

整合素信号传导的内源性抑制

• 批准号: 9036653
• 负责人: ULHAS P NAIK
• 金额: $ 9.73万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9036653
• 关键词: Endogenous; suppression; integrin; signaling

DESCRIPTION (provided by applicant): Platelets are anucleated cells found in abundance in circulation and play an important role in the process of physiological hemostasis. However, unwanted platelet activation results in a pathological condition termed thrombosis, which is the root cause of major cardiovascular diseases such as myocardial infarction and stroke. During vascular injury, circulating platelets adhere to the exposed subendothelial proteins such as collagen and are activated. Activated platelets recruit more platelets by secreting ADP from their granules and by generation of thromboxane A2. Activated platelets form a stable plug through fibrinogen-dependent crosslinking of integrin �IIb�3. This process is tightly regulated and any defect in this regulation can result in impaired platelet activation resulting in bleeding disorder. For this reason, understanding the mechanisms surrounding platelet activation is essential. Platelets are kept in an unstimulated state by little-known anti-stimulatory mechanisms. During vascular injury, pro-stimulatory mechanisms, such as signaling by various physiological agonists, override the anti-stimulatory machinery to achieve platelet aggregation. We have identified a novel protein named JAM-A, which is expressed on platelets and negatively regulates platelet function. JAM-A binds to integrin �IIb�3 and suppresses its activation and signaling. How the interaction of JAM-A with the integrin affects platelet function is not well understood and is the focus of this proposed application. We hypothesize that JAM-A is an endogenous inhibitor of integrin activation, and affects integrin outside in signaling. To test thi hypothesis, we will use Jam-A knockout mice and evaluate the molecular mechanisms through which JAM-A suppresses platelet activation and thus thrombosis.

描述（由申请方提供）：血小板是循环中大量存在的无核细胞，在生理止血过程中发挥重要作用。然而，不需要的血小板活化导致称为血栓形成的病理状况，其是主要心血管疾病如心肌梗塞和中风的根本原因。在血管损伤期间，循环血小板粘附于暴露的内皮下蛋白质如胶原蛋白并被激活。活化的血小板通过从颗粒中分泌ADP和产生血栓素A2来募集更多的血小板。活化的血小板通过纤维蛋白原依赖性的整合素IIb 3交联形成稳定的血栓。该过程受到严格调控，该调控中的任何缺陷都可能导致血小板活化受损，从而导致出血性疾病。因此，了解血小板活化的机制至关重要。血小板通过鲜为人知的抗刺激机制保持在非刺激状态。在血管损伤期间，促刺激机制，例如通过各种生理激动剂的信号传导，超越抗刺激机制以实现血小板聚集。我们已经鉴定了一种名为JAM-A的新蛋白，其在血小板上表达并负调节血小板功能。JAM-A与整合素IIb 3结合并抑制其活化和信号传导。JAM-A与整联蛋白的相互作用如何影响血小板功能还没有很好地理解，并且是本申请的焦点。我们假设JAM-A是整合素激活的内源性抑制剂，并且在信号传导中影响整合素外部。为了验证这一假设，我们将使用Jam-A基因敲除小鼠并评估JAM-A抑制血小板活化从而抑制血栓形成的分子机制。