The central hypothesis of the University of Utah Molecular Medicine Translation Research Center in Thrombosis (U2M2-TRCT) is that the systemic metabolic milieu reprograms platelets into cells that display a prothrombotic phenotype. As part of this programmatic theme, project 1 will begin defining the molecular mechanisms that control reprogramming events in megakaryocytes and platelets. Project 1 is supported by next-generation RNA-sequencing and functional data in platelets isolated from obese and diabetic humans and mice. Specifically, we show that the metabolic milieu induces profound changes in the molecular signature and function of platelets. It is our contention that these changes are not random: instead, we believe that distinct molecular mechanisms reprogram gene expression in megakaryocytes and platelets. One control checkpoint, which we will test in project 1, involves regulation by microRNAs (miRNAs). ' Three specific aims will be used to examine how obesity and diabetes reprograms the molecular signature and function of platelets. In the first aim and in coordination with project 2, we will determine if diet-induced obesity, obesity followed by weight loss, and therapeutic correction of systemic metabolic imbalances alters reprogramming events in mouse platelets.
The first aim will also incorporate corollary studies in human patients with metabolic syndrome.
In aim 2, we will determine the role of precursor miRNA processing in regulating platelet reprogramming and function using mice whose platelets lack Dicer, an RNase III enzyme that is central to the production of mature miRNAs. In the final aim, we will determine how miRNAs regulate the expression of mitochondrial transcripts/proteins (uncoupling protein 2 and mitofusin 2) that are upregulated in platelets isolated from obese mice and humans. Data generated from Aim 3 will directly compliment project 2, which tests the functionality of these mitochondrial targets, and projects 3 and 4 that characterize their expression patterns in platelets isolated from humans with metabolic syndrome. Thus, project 1 will contribute to all facets of the U2M2-TRCT program as it reveals new insights into how the metabolic milieu influences the molecular signature and function of platelets.

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 #
8464243
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
$328,373
Indirect Cost
$108,112
Name
University of Utah
Department
Type
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
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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
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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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