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 #
5U54HL112311-03
Application #
8656418
Study Section
Special Emphasis Panel (ZHL1)
Project Start
Project End
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Utah
Department
Type
DUNS #
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
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Fidler, Trevor P; Campbell, Robert A; Funari, Trevor et al. (2017) Deletion of GLUT1 and GLUT3 Reveals Multiple Roles for Glucose Metabolism in Platelet and Megakaryocyte Function. Cell Rep 21:1705
Zeller Meidell, Krystin; Robinson, Ryan; Vieira-de-Abreu, Adriana et al. (2017) RGDfK-functionalized gold nanorods bind only to activated platelets. J Biomed Mater Res A 105:209-217
Michael, James V; Wurtzel, Jeremy G T; Mao, Guang Fen et al. (2017) Platelet microparticles infiltrating solid tumors transfer miRNAs that suppress tumor growth. Blood 130:567-580
Pannucci, Christopher J; Rondina, Matthew T (2017) Should we be following anti-factor Xa levels in patients receiving prophylactic enoxaparin perioperatively? Surgery 161:329-331

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