This project focuses on gaps in our knowledge regarding molecular mechanisms by which platelets become pro-thrombotic in diabetes and in a key associated metabolic condition, obesity. Our studies have major clinical and translational significance because atherothrombosis and other thrombotic syndromes, including venous thrombosis and pulmonary embolism, are common and morbid complications of type 2 diabetes mellitus (DM) and obesity. Although the mechanisms have not been defined, there are substantial published observations indicating that platelets are hyperreactive and insulin resistant in these conditions. A central thematic hypothesis in the University of Utah Molecular Medicine Translational Research Center in Thrombosis (U2M2-TRCT), which we have established in response to this NHLBI initiative to develop translational programs in thrombotic and hemostatic disorders, is that changes in the systemic milieu of patients with metabolic syndromes leads to reprogramming of platelets, resulting in prothrombotic and dysfunctional activities. This hypothesis is based on extensive preliminary data generated from studies of human platelets and platelets in experimental models by U2M2-TRCT investigators. This project will examine the central hypothesis in subjects with type 2 DM and obesity, providing a rigorous test in the """"""""human model"""""""" that complements pre-clinical studies in Projects 1 and 2 and additional novel clinical analysis in Project 4.
Aim 1 will prospectively determine if platelet reprogramming occurs in type 2 DM and obesity, and Aim 2 will determine if reprogramming can be reversed by intervention with an agent with a unique therapeutic profile that has been extensively examined and used in the clinic, metformin. Our studies will provide critical translational observations that will be tightly integrated with discoveries in Projects 1, 2, and 4, and will also be an important vehicle for research career development activities of new and emerging translational investigators.

Public Health Relevance

Patients with type 2 diabetes, obesity, or the metabolic syndrome are at increased risk for blood clots (thrombosis) caused by cells called platelets. Our studies will determine how metabolic factors in the blood and tissues (the metabolic milieu), such as high glucose and lipids, make platelets more prone to induce thrombosis, providing new insights into the treatment and management of diabetes and obesity.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54HL112311-02
Application #
8464246
Study Section
Special Emphasis Panel (ZHL1-CSR-C)
Project Start
Project End
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
2
Fiscal Year
2013
Total Cost
$153,582
Indirect Cost
$50,696
Name
University of Utah
Department
Type
DUNS #
009095365
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
Morales-Ortíz, Jessica; Deal, Victoria; Reyes, Fiorella et al. (2018) Platelet-derived TLT-1 is a prognostic indicator in ALI/ARDS and prevents tissue damage in the lungs in a mouse model. Blood 132:2495-2505
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
Morales-Ortíz, Jessica; Rondina, Matthew T; Brown, Samuel M et al. (2018) High Levels of Soluble Triggering Receptor Expressed on Myeloid Cells-Like Transcript (TLT)-1 Are Associated With Acute Respiratory Distress Syndrome. Clin Appl Thromb Hemost 24:1122-1127
Manne, B K; Rondina, M T (2018) PDK1 governs thromboxane generation and thrombosis in platelets by regulating activation of Raf1 in the MAPK pathway: reply. J Thromb Haemost 16:1904-1905
Cloutier, Nathalie; Allaeys, Isabelle; Marcoux, Genevieve et al. (2018) Platelets release pathogenic serotonin and return to circulation after immune complex-mediated sequestration. Proc Natl Acad Sci U S A 115:E1550-E1559
Manne, B K; Münzer, P; Badolia, R et al. (2018) PDK1 governs thromboxane generation and thrombosis in platelets by regulating activation of Raf1 in the MAPK pathway. J Thromb Haemost 16:1211-1225
Fidler, Trevor P; Rowley, Jesse W; Araujo, Claudia et al. (2017) Superoxide Dismutase 2 is dispensable for platelet function. Thromb Haemost 117:1859-1867
Manne, Bhanu K; Xiang, Shang Chun; Rondina, Matthew T (2017) Platelet secretion in inflammatory and infectious diseases. Platelets 28:155-164
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

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