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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：
8705582
负责人：
ULHAS P NAIK
金额：
$ 28.49万
依托单位：
UNIVERSITY OF DELAWARE
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 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8705582
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 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 public health relevance

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.

描述（申请人提供）：血小板是循环中大量存在的无核细胞，在生理止血过程中起重要作用。然而，不必要的血小板激活导致称为血栓形成的病理状态，这是主要心血管疾病如心肌梗死和中风的根本原因。在血管损伤期间，循环血小板粘附在暴露的内皮蛋白（如胶原蛋白）上并被激活。活化的血小板通过从颗粒中分泌ADP和生成血栓素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交联形成稳定的栓子。这一过程受到严格的调控，而这一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。血小板通过一种鲜为人知的抗刺激机制保持在一种不受刺激的状态。在血管损伤过程中，促刺激机制，如各种生理激动剂的信号传导，覆盖抗刺激机制，实现血小板聚集。我们发现了一种名为JAM-A的新蛋白，它在血小板上表达并负调控血小板功能。JAM-A结合整合素ib1 - 3并抑制其激活和信号传导。JAM-A与整合素的相互作用如何影响血小板功能尚不清楚，这是本应用的重点。我们假设JAM-A是一种内源性整合素激活抑制剂，并影响整合素的外部信号传导。为了验证这一假设，我们将使用Jam-A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。