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.
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.
|Manne, Bhanu K; Xiang, Shang Chun; Rondina, Matthew T (2017) Platelet secretion in inflammatory and infectious diseases. Platelets 28:155-164|
|Kapur, Rick; Kim, Michael; Rebetz, Johan et al. (2017) Low levels of interleukin-10 in patients with transfusion-related acute lung injury. Ann Transl Med 5:339|
|Rezania, Samin; Puskarich, Michael A; Petrusca, Daniela N et al. (2017) Platelet hyperactivation, apoptosis and hypercoagulability in patients with acute pulmonary embolism. Thromb Res 155:106-115|
|Stewart, Lauren K; Nordenholz, Kristen E; Courtney, Mark et al. (2017) Comparison of acute and convalescent biomarkers of inflammation in patients with acute pulmonary embolism treated with systemic fibrinolysis vs. placebo. Blood Coagul Fibrinolysis 28:675-680|
|Fidler, Trevor P; Middleton, Elizabeth A; Rowley, Jesse W et al. (2017) Glucose Transporter 3 Potentiates Degranulation and Is Required for Platelet Activation. Arterioscler Thromb Vasc Biol 37:1628-1639|
|Rodrigues, Rosana S; Bozza, Fernando A; Hanrahan, Christopher J et al. (2017) 18F-fluoro-2-deoxyglucose PET informs neutrophil accumulation and activation in lipopolysaccharide-induced acute lung injury. Nucl Med Biol 48:52-62|
|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|
Showing the most recent 10 out of 95 publications