Ask1 a novel regulator of platelet function

描述（由申请人提供）：人类死亡的首要原因是心血管疾病，如心肌梗死和中风。循环血小板在这些疾病的发病机制中起着重要作用。血小板是一种无核细胞，具有复杂的细胞骨架系统、独特的受体和专门的秘书颗粒。它们大量存在于血液循环中，通过改变形状、分泌颗粒状内容物和聚集对血管损伤作出反应。这对生理性止血的调节是有利的，但对病理性血栓形成是不利的。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和抗刺激机制的严格调控。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。我们已经确定了一种新的血小板蛋白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，并将信号传递给血小板纤维蛋白原受体复合物，并帮助协调调节血小板聚集和血栓形成的刺激信号。该建议的重点是了解ASK1调节的分子机制，以调节血小板活化。这种调节机制的识别和表征可能为开发潜在的治疗血栓性疾病的药物确定新的靶点。

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.