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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL066277-02
Application #
6537937
Study Section
Hematology Subcommittee 2 (HEM)
Program Officer
Ganguly, Pankaj
Project Start
2001-07-01
Project End
2005-06-30
Budget Start
2002-07-01
Budget End
2003-06-30
Support Year
2
Fiscal Year
2002
Total Cost
$262,500
Indirect Cost
Name
University of Utah
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Schwertz, Hansjörg; Rowley, Jesse W; Schumann, Gerald G et al. (2018) Endogenous LINE-1 (Long Interspersed Nuclear Element-1) Reverse Transcriptase Activity in Platelets Controls Translational Events Through RNA-DNA Hybrids. Arterioscler Thromb Vasc Biol 38:801-815
Middleton, Elizabeth A; Rondina, Matthew T; Schwertz, Hansjorg et al. (2018) Amicus or Adversary Revisited: Platelets in Acute Lung Injury and Acute Respiratory Distress Syndrome. Am J Respir Cell Mol Biol 59:18-35
Campbell, Robert A; Vieira-de-Abreu, Adriana; Rowley, Jesse W et al. (2017) Clots Are Potent Triggers of Inflammatory Cell Gene Expression: Indications for Timely Fibrinolysis. Arterioscler Thromb Vasc Biol 37:1819-1827
Nance, D; Campbell, R A; Rowley, J W et al. (2016) Combined variants in factor VIII and prostaglandin synthase-1 amplify hemorrhage severity across three generations of descendants. J Thromb Haemost 14:2230-2240
Rondina, M T; Freitag, M; Pluthero, F G et al. (2016) Non-genomic activities of retinoic acid receptor alpha control actin cytoskeletal events in human platelets. J Thromb Haemost 14:1082-94
Yost, Christian C; Schwertz, Hansjörg; Cody, Mark J et al. (2016) Neonatal NET-inhibitory factor and related peptides inhibit neutrophil extracellular trap formation. J Clin Invest 126:3783-3798
Rondina, Matthew T; Carlisle, McKenzie; Fraughton, Tamra et al. (2015) Platelet-monocyte aggregate formation and mortality risk in older patients with severe sepsis and septic shock. J Gerontol A Biol Sci Med Sci 70:225-31
Rondina, M T; Weyrich, A S (2015) Regulation of the genetic code in megakaryocytes and platelets. J Thromb Haemost 13 Suppl 1:S26-32
Hottz, Eugenio D; Medeiros-de-Moraes, Isabel M; Vieira-de-Abreu, Adriana et al. (2014) Platelet activation and apoptosis modulate monocyte inflammatory responses in dengue. J Immunol 193:1864-72
Madden, Jesse L; Drakos, Stavros G; Stehlik, Josef et al. (2014) Baseline red blood cell osmotic fragility does not predict the degree of post-LVAD hemolysis. ASAIO J 60:524-8

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