Novel signaling molecules regulating platelet activation

调节血小板活化的新型信号分子

• 批准号: 10393576
• 负责人: Satya P. Kunapuli
• 金额: $ 94万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10393576
• 关键词: Age; Applications Grants; Atherosclerosis; Blood Platelets; Blood Vessels; Blood flow; Cells; Chronic Lymphocytic Leukemia; Diabetes Mellitus; Disease; Environment; Event; Focus Groups; Funding; Genetic; Goals; Hemostatic function; Inflammation; Lesion; Malignant Neoplasms; Mediating; MicroRNAs; Paper; Pathway interactions; Platelet Activation; Play; Protein Kinase; Protein Tyrosine Kinase; Publishing; Reagent; Regulation; Research; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Surface; System; TEC Protein Tyrosine Kinase; Therapeutic Agents; Thrombocytopenia; Thrombosis; Tyrosine Phosphorylation; United States National Institutes of Health; Work; insight; kinase inhibitor; lymphatic vessel; new therapeutic target; novel; platelet function; receptor; receptor-mediated signaling; thrombotic; tool

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.

血小板在止血和血栓形成中发挥着至关重要的作用，越来越多的研究表明其 在炎症、癌症和动脉粥样硬化等其他疾病状态中的作用 血小板表达 表面受体的数量，通过它们的激活，使血小板能够解释其局部 环境并检测血管病变并促进止血。我的小组专注于这些 信号传导步骤以及它们的相互作用如何介导血小板激活。了解信令网络 在过去的二十年里，它们的监管一直是我的研究重点，我们的小组已经做出了 对血小板信号传导领域做出了重要贡献。我的研究目标是识别新的信号传导 调节主要信号传导途径的分子，表征新的信号传导途径 来自相同的信号分子，了解各种酪氨酸激酶的差异 血小板中的通路。我的额外目标是了解血小板发生了什么变化 组成，包括 miRNA，随着年龄和疾病（例如糖尿病）的变化，使它们更 易发生血栓事件。这项工作建立在我们过去在该领域的贡献和许多 我们积累的试剂和遗传工具。在这个提案中，我们特别强调 调节信号分子的细胞内相互作用。该研究的新颖之处之一 提出的是相同的蛋白激酶，通过不同的酪氨酸磷酸化，激活 不同的信号通路在止血中具有不同的作用。本文提出的研究 应用将为新信号传导的调控和识别提供进一步的见解 血小板中的途径，这可能适用于表达类似受体的其他细胞系统 可以为治疗血栓形成和血小板减少症的新治疗靶点奠定基础。在 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 可能干扰这些途径的治疗药物的可能影响。例如， 我们的研究预计 Ibrutinib（一种 Tec 激酶抑制剂）可用于治疗慢性 淋巴细胞白血病，会阻断血小板中的 CLEC2 通路，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来实现这些目标 过去二十年来一直在工作。 NIH 在血小板上资助了大约 22 年 信号范式，已发表 180 多篇论文（平均每年 8 篇）。这 OIA 将减少向各个机构单独提交专题拨款申请的需要 连贯的具体目标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如何- 可以操纵介导的信号传导来控制血小板功能。