The overall goal of the University of Utah Molecular Medicine Translational Research Center in Thrombosis (U2M2-TRCT) is to test the hypothesis that the abnormal metabolic milieu in type 2 diabetes (T2DM) and the metabolic syndrome (MS) leads to genetic and metabolic reprogramming of platelets. This reprogramming directly contributes to the increase in platelet activation that characterizes these subjects who are at increased risk for thrombosis. The specific focus of project 2 is to elucidate the mechanisms that are responsible for the metabolic reprograming that develops in platelets of humans and mouse models of T2DM and the MS, and to determine if the associated changes in platelet metabolism will directly contribute to platelet dysfunction. Our preliminary studies reveal that diabetes alters metabolome profiles of platelets with changes consistent with increased glycolysis and TCA (tricarboxylic acid) flux and accumulation of lipid intermediates. In addition, transcriptional profiling reveals significant changes in the expression of genes that regulate mitochondrial energetics, coupling efficiency (e.g. UCP2) and mitochondrial dynamics (e.g. Mfn2). Thus we hypothesize that the metabolic milieu of T2DM and the MS increases platelet glucose utilization and mitochondrial metabolism that induces mitochondrial oxidative stress, leading to platelet activation.
In aim 1 we will test the hypothesis that T2DM and the MS leads to mitochondrial dysfunction, characterized by mitochondrial uncoupling, ROS overproduction and impaired mitochondrial dynamics.
In aim 2 we will determine the mechanisms by which T2DM and the MS alter mitochondrial function and will test the hypothesis that manipulation of these mechanisms (i.e., KO of platelet superoxide dismutase 2, UCP2 and Mfn2) are sufficient to modulate platelet activity.
In aim 3 we will determine the contribution of increased platelet glucose utilization to platelet hyperactivation in T2DM and the MS. This hypothesis will be addressed in studies of diabetic murine models with genetic reduction or augmentation in platelet glucose transport. Collectively these studies will shed new insight into mechanisms that alter platelet metabolism and function in obesity and diabetes.

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)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54HL112311-03
Application #
8656417
Study Section
Special Emphasis Panel (ZHL1)
Project Start
Project End
Budget Start
Budget End
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
Koupenova, Milka; Vitseva, Olga; MacKay, Christopher R et al. (2014) Platelet-TLR7 mediates host survival and platelet count during viral infection in the absence of platelet-dependent thrombosis. Blood 124:791-802
Schubert, Sebastian; Weyrich, Andrew S; Rowley, Jesse W (2014) A tour through the transcriptional landscape of platelets. Blood 124:493-502
Clancy, Lauren; Freedman, Jane E (2014) New paradigms in thrombosis: novel mediators and biomarkers platelet RNA transfer. J Thromb Thrombolysis 37:12-6
Freedman, Jane E (2014) Inherited dysfunctional nitric oxide signaling and the pathobiology of atherothrombotic disease. Circ Res 114:1372-3
Major, Heather D; Campbell, Robert A; Silver, Robert M et al. (2014) Synthesis of sFlt-1 by platelet-monocyte aggregates contributes to the pathogenesis of preeclampsia. Am J Obstet Gynecol 210:547.e1-7
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
Shi, Dallas S; Smith, Matthew C P; Campbell, Robert A et al. (2014) Proteasome function is required for platelet production. J Clin Invest 124:3757-66
Chen, Karin; Coonrod, Emily M; Kumanovics, Attila et al. (2013) Germline mutations in NFKB2 implicate the noncanonical NF-*B pathway in the pathogenesis of common variable immunodeficiency. Am J Hum Genet 93:812-24
Franks, Zechariah; Campbell, Robert A; Vieira de Abreu, Adriana et al. (2013) Methicillin-resistant Staphylococcus aureus-induced thrombo-inflammatory response is reduced with timely antibiotic administration. Thromb Haemost 109:684-95
Freedman, Jane E; Tanriverdi, Kahraman (2013) Defining miRNA targets: balancing simplicity with complexity. Circulation 127:2075-7