Novel signaling molecules regulating platelet activation

点击翻译按钮获取中文摘要

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.