Novel signaling molecules regulating platelet activation

血小板在止血和血栓形成中起着至关重要的作用，越来越多的研究表明其 在包括炎症、癌症和动脉粥样硬化在内的其他疾病状态中的作用 一些表面受体，通过它们的激活，允许血小板解释其局部 环境和检测血管损伤和促进止血。我的团队专注于以下几点 信号步骤及其相互作用如何调节血小板激活。了解信令网络 在过去的二十年里，他们的监管一直是我的研究重点，我们团队已经做出了 对血小板信号领域的重要贡献。我的研究目标是识别新的信号 调节主要信号通路的分子，表征了新的信号通路 来自相同的信号分子，并了解不同酪氨酸激酶的差异 血小板中的通路。我的另一个目标是了解血小板发生了什么变化 组成，包括miRNAs，与年龄和疾病，如糖尿病，使它们更 容易发生血栓事件的。这项工作建立在我们过去在该领域的贡献和许多 我们积累起来的试剂和基因工具。在这项建议中，我们特别强调 调节信号分子的细胞内相互作用。这项研究的新奇之处之一 提出的是，相同的蛋白激酶，通过差异酪氨酸磷酸化，激活 不同的信号通路，在止血中有不同的作用。在这篇文章中提出的研究 应用将为调节和识别新的信号提供进一步的见解 血小板中的通路，这可能适用于表达类似受体和 可形成治疗血栓形成和血小板减少症的新的治疗靶点。在……里面 此外，了解血小板中的这些信号级联将有助于我们评估和预测 可能干扰这些通路的治疗剂的可能含义。例如, 我们的研究预计，伊布鲁替尼，一种Tec激酶抑制剂，用于治疗慢性阻塞性肺疾病 淋巴细胞性白血病，会阻断血小板中的CLEC2途径，导致血液流入淋巴管 船只。我希望在未来十年以同样的活力和强度追求这些目标 在过去的二十年里雇佣了很多人。已经由NIH资助了大约22年的血小板研究 并发表了180多篇论文(平均每年8篇)。这个 内审办将减少向不同机构分别提交专题赠款申请的需要，这些机构包括 一致的具体目标，并将使我们能够为理解 血小板信号网络。我们的首要目标是了解受体网络是如何- 介导的信号可以被操纵来控制血小板的功能。

Platelets play a crucial role in hemostasis and thrombosis, and more and more studies indicate their role in other disease states including inflammation, cancer, and atherosclerosis Platelets express a number of surface receptors, which through their activation, allow platelets to interpret their local environment and to detect vascular lesions and promote hemostasis. My group focuses on these signaling steps and how their interplay mediates platelet activation. Understanding signaling networks and their regulation has been my research focus for the past two decades and our group has made important contributions to the platelet-signaling field. My research goals are to identify novel signaling molecules that regulate main signaling pathways, characterize novel signaling pathways emanating from the same signaling molecule, and understand the differences in various tyrosine kinase pathways in platelets. My additional goals are to understand what changes occur in platelet composition, including miRNAs, with age and disease, such as diabetes, that make them more susceptible to thrombotic events. This work builds on our past contributions in the field and a host of reagents and genetic tools that we have amassed. In this proposal, we place particular emphasis on the intracellular interactions that regulate a signaling molecule. One of the novelties of the studies proposed is that the same protein kinase, through differential tyrosine phosphorylation, activates diverse signaling pathways, which have distinct roles in hemostasis. The studies proposed in this application will provide further insights into the regulation and identification of novel signaling pathways in platelets, which may be applicable to other cell systems expressing similar receptors and could form the basis for novel therapeutic targets to treat thrombosis and thrombocytopenia. In addition, understanding these signaling cascades in platelets will help us evaluate and predict possible implications of the therapeutic agents that could interfere with these pathways. For example, our studies anticipate that Ibrutinib, a Tec kinase inhibitor used for the treatment of chronic lymphocytic leukemia, will block the CLEC2 pathway in platelets and cause blood flow into lymphatic vessels. I would like to pursue these goals in the next decade with the same vigor and intensity that have employed in the past two decades. have been funded by NIH for about 22 years on the platelet signaling paradigms and have published over 180 papers (on an average of 8 papers a year). The OIA will alleviate the need to submit separate thematic grant applications to various agencies with coherent specific aims and will allow us to make significant contributions to the understanding of platelet signaling networks. Our overarching goal is to understand how the network of receptor- mediated signaling can be manipulated to control platelet function.