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Endogenous suppression of integrin signaling

整合素信号传导的内源性抑制

基本信息

批准号：
8856656
负责人：
ULHAS P NAIK
金额：
$ 38.4万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
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/8856656
关键词：
Ablation Adaptor Signaling Protein Adoptive Transfer Affect Affinity Affinity Chromatography Agonist Binding Biological Assay Blood Circulation Blood Platelets Blood Vessels Bone Marrow Cells Cardiovascular Diseases Cells Coagulation Process Collagen Complex Cues Cytoplasmic Granules Cytoplasmic Tail Data Defect Disease Fibrinogen Fibrinogen Receptors Fluorescence Fluorescence Resonance Energy Transfer Generations Health Hemorrhage Hemostatic function Immunoglobulins In Vitro Injury Integrin Inhibition Integrins Knock-in Mouse Knockout Mice Lasers Molecular Mus Mutation Myocardial Infarction Names Phenotype Phosphopeptides Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Physiological Physiological Processes Plant Roots Platelet Activation Platelet aggregation Play Process Proteins Recruitment Activity Regulation Rest Role SRC gene Scaffolding Protein Serine Signal Transduction Signaling Molecule Site-Directed Mutagenesis Stroke System Techniques Testing Therapeutic Intervention Thrombosis Thromboxane A2 Thrombus Tyrosine Tyrosine Phosphorylation Wound Healing arteriole combat crosslink in vivo in vivo Model inhibitor/antagonist junctional adhesion molecule mutant new therapeutic target novel protein complex

项目摘要

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.

说明(申请人提供)：血小板是在血液循环中大量发现的无核细胞，在生理止血过程中发挥重要作用。然而，不想要的血小板激活会导致一种名为血栓的病理状态，这是心肌梗死和中风等主要心血管疾病的根本原因。在血管损伤期间，循环中的血小板附着于暴露的内皮下蛋白，如胶原蛋白，并被激活。活化的血小板通过从其颗粒中分泌ADP和通过产生血栓素A2来招募更多的血小板。活化的血小板通过纤维蛋白原依赖的整合素�IIb�3的交联形成稳定的塞子。这一过程受到严格的调控，这一调控的任何缺陷都可能导致血小板活化受损，导致出血紊乱。因此，了解围绕着血小板激活的机制是至关重要的。通过鲜为人知的抗刺激机制，血小板保持在未受刺激的状态。在血管损伤期间，促刺激机制，如由各种生理激动剂发出的信号，凌驾于反刺激机制之上，以实现血小板聚集。我们已经鉴定出一种新的蛋白JAM-A，它表达在血小板上，对血小板功能起负向调节作用。JAM-A与整合素�IIb�3结合并抑制其激活和信号转导。JAM-A与整合素的相互作用如何影响血小板功能还不是很清楚，这是这项拟议应用的重点。我们假设JAM-A是整合素激活的内源性抑制物，并在信号转导中影响外部整合素。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抑制血小板激活从而抑制血栓形成的分子机制。