The broad objective of the University of Utah Molecular Medicine Translation Research Center in Thrombosis (U2M2-TRCT) is to dissect novel clinical and molecular determinants of thrombotic risk in patients with metabolic disorders (obesity, diabetes, and the metabolic syndrome). The U2M2-TRCT unites a group of basic and clinical investigators with breadth and expertise in thrombosis and metabolic dysregulation. Our studies will test the thematic hypothesis that metabolic changes in the systemic milieu reprogram platelet precursors and platelets themselves, resulting in altered thrombotic activities of these critical cells. To examin this central theme, we propose four research projects and four cores and studies by a cadre of established and emerging investigators with proven track records of productive interactions. The intellectual infrastructure is as follows: Project 1, The Molecular Regulation of Platelet Reprogramming by the Metabolic Milieu, characterizes reprogramming events in platelets and dissects the mechanisms by which microRNAs influence platelet phenotypes in metabolic syndromes;Project 2, Metabolic Regulation of Platelet Reprogramming, will determine how genetic manipulation of glucose transporters and modulators of mitochondrial function regulate reprogramming events and functional activities of platelets;Project 3, The Role of the Metabolic Milieu in Regulating Platelet Reprogramming in Humans, prospectively examines platelet reprogramming and platelet hyperreactivity imposed by the metabolic milieu of type 2 diabetes. Project 3 will also determine if therapeutic correction of metabolic imbalances reverses platelet reprogramming and hyperactivity;Project 4, Platelet Reprogramming in Human Obesity and Diabetes, will evaluate platelet reprogramming and function in subjects exposed to acute triglyceride emulsion infusion, obese subjects before and after bariatric surgery, and patients enrolled in the Framingham Heart Study. Screening of an early-phase translation mRNA nanochip in humans with metabolic syndromes is a key feature in Project 4. Together, our translational studies will explore new paradigms in thrombosis and metabolic syndromes, and will be a unique platform for research career development.

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 #
8464229
Study Section
Special Emphasis Panel (ZHL1-CSR-C (F1))
Program Officer
Link, Rebecca P
Project Start
2012-05-01
Project End
2017-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
2
Fiscal Year
2013
Total Cost
$2,523,992
Indirect Cost
$622,340
Name
University of Utah
Department
Internal Medicine/Medicine
Type
Schools of Medicine
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
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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