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)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54HL112311-03
Application #
8656417
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
Rondina, Matthew T; Tatsumi, Kohei; Bastarache, Julie A et al. (2016) Microvesicle Tissue Factor Activity and Interleukin-8 Levels are Associated with Mortality in Patients with Influenza A/H1N1 Infection. Crit Care Med 44:e574-8
Freedman, Jane E; Gerstein, Mark; Mick, Eric et al. (2016) Diverse human extracellular RNAs are widely detected in human plasma. Nat Commun 7:11106
Yoo, Jae Hyuk; Shi, Dallas S; Grossmann, Allie H et al. (2016) ARF6 Is an Actionable Node that Orchestrates Oncogenic GNAQ Signaling in Uveal Melanoma. Cancer Cell 29:889-904
Yost, Christian C; Schwertz, Hansjörg; Cody, Mark J et al. (2016) Neonatal NET-inhibitory factor and related peptides inhibit neutrophil extracellular trap formation. J Clin Invest 126:3783-3798
Koliopoulou, Antigone; McKellar, Stephen H; Rondina, Matthew et al. (2016) Bleeding and thrombosis in chronic ventricular assist device therapy: focus on platelets. Curr Opin Cardiol 31:299-307
Stubblefield, William B; Alves, Nathan J; Rondina, Matthew T et al. (2016) Variable Resistance to Plasminogen Activator Initiated Fibrinolysis for Intermediate-Risk Pulmonary Embolism. PLoS One 11:e0148747
Shih, Lauren; Kaplan, David; Kraiss, Larry W et al. (2016) Platelet-Monocyte Aggregates and C-Reactive Protein are Associated with VTE in Older Surgical Patients. Sci Rep 6:27478
Araújo, Cláudia V; Campbell, Clarissa; Gonçalves-de-Albuquerque, Cassiano F et al. (2016) A PPARγ AGONIST ENHANCES BACTERIAL CLEARANCE THROUGH NEUTROPHIL EXTRACELLULAR TRAP FORMATION AND IMPROVES SURVIVAL IN SEPSIS. Shock 45:393-403
Rowley, Jesse W; Chappaz, Stéphane; Corduan, Aurélie et al. (2016) Dicer1-mediated miRNA processing shapes the mRNA profile and function of murine platelets. Blood 127:1743-51
Beaulieu, Lea M; Vitseva, Olga; Tanriverdi, Kahraman et al. (2016) Platelet functional and transcriptional changes induced by intralipid infusion. Thromb Haemost 115:1147-56

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