Research Departments & Organizations
We wish to determine why patients with diabetes mellitus have increased vascular thrombosis. We use a combination of approaches including molecular signaling, biochemistry, genomics and proteomics on both human subjects and animal models. The ultimate goal is to develop novel mechanistic based therapies.
We have also been exploring the role of platelets in non-small-cell lung carcinoma (NSCLC) - both how platelets are influenced by the NSCLC, and how platelets can influence the progression of NSCLC.
Specialized Terms: Platelets; Diabetes Mellitus; Atherothrombosis; Prostacyclin; Thromboxane; NSAIDs
Extensive Research Description
The Hwa Laboratory research interests are on eicosanoids and diabetes mellitus, and include a number of large collaborative efforts within Yale and externally. All are focused in the broad areas of eicosanoids, NSAIDs and the development of thrombus on a background of atherosclerosis (atherothrombosis). Our studies extend from fundamental structure function of GPCRs, to pharmacogenetics, molecular signaling, pathophysiology, and clinical outcomes. For our studies we use a number of models including tissue culture cells, platelets, vascular smooth muscle cells, mouse knockout and transgenics, and recruited human patients. Our current studies can be broadly divided into the following major areas.
1) Pharmacogenetics of the prostanoid receptors
2) Platelet dysfunction in diabetes mellitus
3) miRNA regulation of thrombosis
4) The Yale cardiovascular tissue repository collaborative effort
Inducing mitophagy in diabetic platelets protects against severe oxidative stress.
Lee SH, Du J, Stitham J, Atteya G, Lee S, Xiang Y, Wang D, Jin Y, Leslie KL, Spollett G, Srivastava A, Mannam P, Ostriker A, Martin KA, Tang WH, Hwa J. Inducing mitophagy in diabetic platelets protects against severe oxidative stress. EMBO Molecular Medicine 2016, 8:779-95. 2016
Hyperglycemia repression of miR-24 coordinately upregulates endothelial cell expression and secretion of von Willebrand factor.
Xiang Y, Cheng J, Wang D, Hu X, Xie Y, Stitham J, Atteya G, Du J, Tang WH, Lee SH, Leslie K, Spollett G, Liu Z, Herzog E, Herzog RI, Lu J, Martin KA, Hwa J. Hyperglycemia repression of miR-24 coordinately upregulates endothelial cell expression and secretion of von Willebrand factor. Blood 2015, 125:3377-87. 2015
Aldose reductase-mediated phosphorylation of p53 leads to mitochondrial dysfunction and damage in diabetic platelets.
Tang WH, Stitham J, Jin Y, Liu R, Lee SH, Du J, Atteya G, Gleim S, Spollett G, Martin K, Hwa J. Aldose reductase-mediated phosphorylation of p53 leads to mitochondrial dysfunction and damage in diabetic platelets. Circulation 2014, 129:1598-609. 2014
A form of the metabolic syndrome associated with mutations in DYRK1B.
Keramati AR, Fathzadeh M, Go GW, Singh R, Choi M, Faramarzi S, Mane S, Kasaei M, Sarajzadeh-Fard K, Hwa J, Kidd KK, Babaee Bigi MA, Malekzadeh R, Hosseinian A, Babaei M, Lifton RP, Mani A. A form of the metabolic syndrome associated with mutations in DYRK1B. The New England Journal Of Medicine 2014, 370:1909-1919. 2014
Ten-eleven translocation-2 (TET2) is a master regulator of smooth muscle cell plasticity.
Liu R, Jin Y, Tang WH, Qin L, Zhang X, Tellides G, Hwa J, Yu J, Martin KA. Ten-eleven translocation-2 (TET2) is a master regulator of smooth muscle cell plasticity. Circulation 2013, 128:2047-57. 2013
Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome.
Lemaire M, Frémeaux-Bacchi V, Schaefer F, Choi M, Tang WH, Le Quintrec M, Fakhouri F, Taque S, Nobili F, Martinez F, Ji W, Overton JD, Mane SM, Nürnberg G, Altmüller J, Thiele H, Morin D, Deschenes G, Baudouin V, Llanas B, Collard L, Majid MA, Simkova E, Nürnberg P, Rioux-Leclerc N, Moeckel GW, Gubler MC, Hwa J, Loirat C, Lifton RP. Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome. Nature Genetics 2013, 45:531-6. 2013
Glucose and collagen regulate human platelet activity through aldose reductase induction of thromboxane.
Tang WH, Stitham J, Gleim S, Di Febbo C, Porreca E, Fava C, Tacconelli S, Capone M, Evangelista V, Levantesi G, Wen L, Martin K, Minuz P, Rade J, Patrignani P, Hwa J. Glucose and collagen regulate human platelet activity through aldose reductase induction of thromboxane. The Journal Of Clinical Investigation 2011, 121:4462-76. 2011