Massachusetts General Hospital

Research Areas

• Modulation of mevalonate pathway and sepsis
• Burn injury-induced insulin resistance and muscle wasting
• Inducible nitric oxide synthase in stress- and obesity-induced insulin resistance and diabetes

Description of Research
The research efforts in my research team have been focused on acute and chronic activation of stress/inflammatory signaling pathways in human diseases, including sepsis, major trauma (e.g., burn injury), and obesity-induced diabetes. Inflammation has been implicated in the pathogenesis of many human diseases. Despite intense investigation for a number of years, two fundamental questions remain to be determined: (1) How activation of inflammatory/stress signaling pathways is initiated and sustained; and (2) What are downstream executioners by which inflammation mediates human diseases.

To identify novel molecular targets to control inflammatory/stress responses, my research team has been testing the hypotheses that: (a) inducible nitric oxide synthase (iNOS) and dysregulated protein S-nitrosylation (the covalent attachment of nitric oxide to reactive cysteine thiols) are a nodal point of the vicious cycle, inflammatory spiral; (b) the mevalonate pathway and protein farnesylation, a lipid modification of cysteine thiols, function as a stress signaling pathway regulating immune function and cell fate in sepsis and burn injury; and (c) insufficiency of coenzyme Q10 (an essential cofactor for electron transport) is a major culprit of mitochondrial dysfunction/ disintegrity in critical illness.

To this end, multidisciplinary approaches have been applied, using molecular and cellular biology, pharmacology, and genetics and proteomics expertise, in my laboratory and in close collaboration with many other research teams. Our research has identified iNOS and protein S-nitrosylation as the major mediator of obesity- and stress-induced insulin resistance, and type 2 diabetes. Recent studies from my laboratory indicate that inhibition of protein farnesylation plays an important role in the statins’ lipid-lowering-independent beneficial effects in sepsis, burn injury, and atherosclerosis. We have been obtaining preclinical results and observational clinical data to help develop new strategies to improve the clinical outcome of critically ill patients (e.g., sepsis, burn injury) and chronic inflammation-mediated human diseases (e.g., diabetes).

Grant Funding
Research Grant #71000 (M Kaneki)                                                Shriners Hospitals for Children                
“Protective Effects of Statin, Coenzyme Q10, and Farnesyltransferase Inhibitor in Post-burn Sepsis”
The goals of this project are to determine the effects of statin-plus-coenzyme Q10 and farnesyltransferase inhibitor on survival following post-burn sepsis and investigate the molecular mechanisms of the protective effects of statins in burned septic mice.
Role: Principal Investigator

Research Grant #85800  (M Kaneki)                                               Shriners Hospitals for Children    
“Role of FoxO transcription factors in burn-induced muscle insulin resistance”                
The goals of this project are to determine the effects of burn injury on FoxO1/3 activities and study the roles of FoxO1/3/4 in burn injury-induced insulin resistance in mice.
Role: Principal Investigator

R01 GM055082-10  (JAJ Martyn)                                                      NIH-NIGMS    
“Molecular pharmacology of insulin resistance in burns”       
This study examines insulin resistance in burns and aberrations in signaling via insulin receptor, with specific focus on the mechanisms of altered signaling via downstream signaling molecules, including insulin receptor, insulin receptor substrate-1, and glucose synthase kinase.
Role: Co-Investigator

Selected Publications

• Yang W, Yamada M, Tamura Y, Chang K, Mao J, Zou L, Feng Y, Kida K, Scherrer-Crosbie M, Chao W, Ichinose F, Yu YM, Fischman AJ, Tompkins RG, Yao S, Kaneki M. Farnesyltransferase inhibitor, FTI-277, reduces mortality of septic mice along with improved bacterial clearance. J Pharmacol Exp Ther. 2011 Dec;339(3):832-41. PMID: 21873557
• Shinozaki, S., Choi, C-S., Shimizu, S., Yamada, M., Kim, M.,  Zhang, T., Dong, H., Kim, Y-B., Kaneki, M. Liver-specific iNOS expression is sufficient to cause hepatic insulin resistance and mild hyperglycemia in mice. J Biol Chem. 2011 Oct 7;286(40):34959-75. PMID: 21846719
• Tanioka, T., Tamura, Y., Fukaya, M., Kim, M., Shimizu, N., Kaneki, M. iNOS and NO donor decrease IRS-2 protein expression by promoting proteasome-dependent degradation in pancreatic b-cells: Involvement of GSK-3b. J Biol Chem. 2011 Aug 19;286(33):29388-96. PMID: 21700708
• Sugita M, Sugita H, Kim M, Mao J, Yasuda Y, Habiro M, Yasuhara S, Shimizu N, Martyn JAJ, Kaneki M. iNOS deficiency ameliorates skeletal muscle insulin resistance but does not alter unexpected lower blood glucose levels after burn injury in C57BL/6 mice. Metabolism. 2012 Jan;61(1):127-36. PMID: 21816442
• Shinozaki, S., Inoue, Y., Yang, W., Fukaya, M., Carter, E.A., Ming-Yu, Y., Fischman, A., Tompkins, R., Kaneki, M. Farnesyltransferase inhibitor improved survival following endotoxin challenge in mice.  Biochem Biophys Res Commun, 2010; 391(3):1459-64. PMID: 20034462

Anesthesia, Critical Care and Pain Medicine

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