Verbatim): The broad, long term goals of this project are to understand how cellular activation regulates gene expression at the translational level. Translational events are critical in the control of cell proliferation, differentiation, and development and have been implicated in malignant transformation, diabetes, and atherosclerosis. However, the mechanisms that control translation have remained relatively uncharacterized, in large part, because transcriptional influences from the nucleus are difficult to eliminate. Here, human platelets are used to study translational events since they are an anucleated cell model that is capable of regulated protein synthesis at the Dost-transcriptional level. An overall hypothesis is that translation of specific mRNAs is regulated by the mammalian target of rapamycin (MTOR) pathway in a signal-dependent fashion. The goal of the first specific aim is to completely characterize the MTOR translational pathway in platelets in regards to its expression. localization, and activation. The second specific aim explores the mechanisms by which integrins regulate mTOR-dependent signaling pathways in platelets.
This aim focuses on beta integrins and the role of integrin- linked kinase as an intracellular molecule that exerts translation control. The third and fourth specific aims characterize a subset of mTOR-dependent mRNAs that are mobilized into polysomes and translated into protein following platelet stimulation. These studies are also conducted in platelets, transfected cell systems. and megakaryocytes. The work proposed will examine new aspects of signal-dependent synthesis and will address critical gaps in our understanding of how gene expression is regulated at the translational level. Moreover, the experiments will yield new information on platelet and megakaryocyte biology and provide insights on how these cells regulate thrombocytopoiesis, hemostasis, pathologic thrombosis, wound repair, and tissue remodeling.
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