Ask1 a novel regulator of platelet function

Ask1 一种新型血小板功能调节剂

基本信息

批准号：
8605910
负责人：
ULHAS P NAIK
金额：
$ 37.49万
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：
2013-02-01 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8605910
关键词：
Ablation Adoptive Transfer Affect Affinity Agonist Binding Biochemical Biological Assay Blood Circulation Blood Platelets Blood Vessels Bone Marrow Cells Cardiovascular Diseases Cause of Death Cells Clot retraction Coagulation Process Complex Cytoplasmic Granules Cytoskeleton Data Defect Disease Event Family Fibrinogen Fibrinogen Receptors Generations Genetic Hemorrhage Hemostatic function Human In Vitro Injury Integrins Knock-in Mouse Lead Life MAP Kinase Kinase Kinase MAP3K5 gene MAPK1 gene MAPK14 gene Membrane Mitogen-Activated Protein Kinases Modeling Molecular Mus Myocardial Infarction Participant Pathogenesis Phenotype Physiological Platelet Activating Factor Platelet Activation Platelet aggregation Play Process Production Proteins Recruitment Activity Regulation Research Role Serotonin Shapes Signal Pathway Signal Transduction Signaling Molecule Stress Stroke Structure-Activity Relationship Techniques Testing Therapeutic Agents Therapy Evaluation Thrombin Thrombosis Thromboxane A2 Thrombus VWF gene Wound Healing combat in vivo in vivo Model mutant novel novel therapeutics public health relevance receptor therapeutic target

项目摘要

DESCRIPTION (provided by applicant): The foremost cause of death in humans is cardiovascular diseases such as myocardial infarction and stroke. Circulating platelets play an important role in the pathogenesis of these diseases. Platelets are anucleated cells with a complex cytoskeletal system, unique receptors, and specialized secretary granules. They are found in the circulation in high abundance, and respond to blood vessel injury by changing shape, secreting granular contents, and aggregation. This is advantageous in the regulation of physiological hemostasis, but can be unfavorable in pathological thrombosis. For this reason, understanding the mechanisms surrounding platelet aggregation is essential. Platelet function is tightly regulated by both pro- and anti-stimulatory mechanisms. 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 platelet protein, ASK1, which appears to be a key participant in the pro-stimulatory mechanism. We hypothesize that ASK1 senses stress and/or pro-stimulatory signals initiated by agonists and transmits signals to the platelet fibrinogen receptor complex and helps in coordinating stimulatory signals that regulate platelet aggregation and thrombus formation. This proposal is focused on understanding the molecular mechanisms that are regulated by ASK1 in order to regulate platelet activation. The identification and characterization of such regulatory mechanisms may define new targets for developing potential therapeutic agents toward thrombotic disorders.

描述（由申请人提供）：人类死亡的首要原因是心血管疾病，例如心肌梗塞和中风。循环血小板在这些疾病的发病机制中发挥着重要作用。血小板是无核细胞，具有复杂的细胞骨架系统、独特的受体和专门的分泌颗粒。它们在循环系统中大量存在，并通过改变形状、分泌颗粒内容物和聚集来应对血管损伤。这有利于生理性止血的调节，但不利于病理性血栓形成。因此，了解血小板聚集的机制至关重要。血小板功能受到促刺激机制和抗刺激机制的严格调节。血小板通过鲜为人知的抗刺激机制保持在未刺激状态。在血管损伤期间，促刺激机制（例如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。我们发现了一种新型血小板蛋白 ASK1，它似乎是促刺激机制的关键参与者。我们假设 ASK1 感知由激动剂引发的应激和/或促刺激信号，并将信号传输至血小板纤维蛋白原受体复合物，并有助于协调调节血小板聚集和血栓形成的刺激信号。该提案的重点是了解 ASK1 调节血小板活化的分子机制。这种调节机制的识别和表征可能会为开发血栓性疾病的潜在治疗剂确定新的目标。