Pulinilkunnil, Thomas - Dalhousie University - Department of Biochemistry & Molecular Biology

研究领域

Proteotoxic Basis for Metabolic Heart Disease One of the major focus of the Pulinilkunnil laboratory is to assess how adaptive or causative changes in protein synthesis and degradation causes heart disease. To maintain cellular homeostasis, synthesized proteins are degraded and recycled inside cellular organelles called lysosomes by a process known as autophagy. Using a multispecies approach (rodents, yeast and zebrafish) Pulinilkunnil lab will specifically examine how different nutrients (glucose, fat and amino acids) influence lysosomal function to alter autophagy. Furthermore investigate whether aberrant lysosomal function impact mitochondrial metabolism and energetics thus governing cardiovascular outcomes in biology and disease. Lysosome Nutrient Sensing and Metabolism in Cancer Pathogenesis Reprogrammed energetics and metabolism is an emerging hallmark of cancer cells. Indeed, altered mitochondrial fuel metabolism contributes to oncogenic mutations which in turn influences cellular signaling and function. Numerous oncogenic processes that are resistant to chemotherapeutics are found to exhibit features of intermittent oxygen and nutrient deprivation, mitochondrial stress, abnormal cell growth and suppressed cellular death. Recent studies have shown that abnormalities in cellular metabolism augment autophagy to facilitate cancer cells to precipitously adapt to environmental stressors by sustaining uninterrupted proliferation thereby evading demise by radiation and/or chemotherapy. Our laboratory is currently elucidating the mechanism by which tumor cell metabolism signals changes in lysosomal autophagy and mechanisms by which this signaling could influence the outcomes of treating cancer. By specifically examining the cross talk between mitochondria and lysosome we hope to uncover novel biochemical pathways that could be targeted selectively to render cancer cells susceptible to first line cancer treatment. Biology of ER Glycosylation in Health and Disease Glycosylation is an extremely important function by which all human cells build sugar chains or glycans that are subsequently attached to other functional molecules, including proteins and lipids. The products of these attachments are called glycoproteins or glycolipids, and are required for the normal growth and function of all tissues and organs. Impairment in glycosylating enzyme disrupts glycan synthesis and metabolism leading to congenital disorder of glycosylation (CDG). Using yeast and zebrafish models Pulinilkunnil lab aims to examine molecular pathways by which impaired glycosylation promotes intracellular distress specifically in organelles like mitochondria, endoplasmic reticulum and lysosomes that are mainly responsible for generating energy, performing quality check on proteins and degrading cellular waste. This research will identify and characterize novel pathways and proteins mediating pathological effects of defective glycosylation. Cardiotoxic Effect of Aquatic Pollutants Aquatic pesticide are endocrine disruptor that continues to persist in the environment despite being discontinued and is associated with increased risks of neurodegenerative disease and breast cancer. Pulinilkunnil laboratory is examining transcriptomic signaling regulating autophagy and mitochondrial energetics in heart, liver, fat and skeletal muscle to aquatic toxicants using zebrafish model

近期论文

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Zhang D, Wang F, Lal N, Chiu AP, Wan A, Jia J, Bierende D, Flibotte S, Sinha S, Asadi A, Hu X, Taghizadeh F, Pulinilkunnil T, Nislow C, Vlodavsky I, Johnson JD, Kieffer TJ, Hussein B, Rodrigues B, (2017) Heparanase Overexpression Induces Glucagon Resistance and Protects Animals From Chemically Induced Diabetes. Diabetes 66(1):45-57 [PubMed] Bartlett JJ, Trivedi PC, Pulinilkunnil T., (2017) Autophagic dysregulation in doxorubicin cardiomyopathy. J. Mol. Cell. Cardiol. 104:1-8 [PubMed] Gawdat K, Legere S, Wong C, Myers T, Marshall JS, Hassan A, Brunt KR, Kienesberger PC, Pulinilkunnil T, Legare JF., (2017) Changes in Circulating Monocyte Subsets (CD16 Expression) and Neutrophil-to-Lymphocyte Ratio Observed in Patients Undergoing Cardiac Surgery. Front Cardiovasc Med. 4:12 [PubMed] D'Souza K, Kane DA, Touaibia M, Kershaw EE, Pulinilkunnil T, Kienesberger PC., (2017) Autotaxin Is Regulated by Glucose and Insulin in Adipocytes. Endocrinology 158(4):791-803 [PubMed] Slade L, Cowie A, Martyniuk CJ, Kienesberger PC, Pulinilkunnil T., (2017) Dieldrin Augments mTOR Signaling and Regulates Genes Associated with Cardiovascular Disease in the Adult Zebrafish Heart (Danio rerio). J Pharmacol Exp Ther. 361(3):375-385 [PubMed] Perez LJ, Rios L, Trivedi P, D'Souza K, Cowie A, Nzirorera C, Webster D, Brunt K, Legare JF, Hassan A, Kienesberger PC, Pulinilkunnil T., (2017) Validation of optimal reference genes for quantitative real time PCR in muscle and adipose tissue for obesity and diabetes research. Sci Rep. 7(1):3612 [PubMed] Trivedi PC, Bartlett JJ, Perez LJ, Brunt KR, Legare JF, Hassan A, Kienesberger PC, Pulinilkunnil T., (2016) Glucolipotoxicity diminishes cardiomyocyte TFEB and inhibits lysosomal autophagy during obesity and diabetes Biochim Biophys Acta. 1861(12 Pt A):1893-1910 [PubMed] Bartlett JJ, Trivedi PC, Yeung P, Kienesberger PC, Pulinilkunnil T., (2016) Doxorubicin Impairs Cardiomyocyte Viability by Suppressing Transcription Factor EB Expression and Disrupting Autophagy Biochem J. BCJ20160385: [PubMed] Dubé JJ, Sitnick MT, Schoiswohl G, Wills RC, Basantani MK, Cai L, Pulinilkunnil T, Kershaw EE., (2015) Adipose triglyceride lipase deletion from adipocytes, but not skeletal myocytes, impairs acute exercise performance in mice. Am J Physiol Endocrinol Metab. : [PubMed] O'Neill HM, Lally JS, Galic S, Pulinilkunnil T, Ford RJ, Dyck JR, van Denderen BJ, Kemp BE, Steinberg GR., (2015) Skeletal muscle ACC2 S212 phosphorylation is not required for the control of fatty acid oxidation during exercise. Physiol Rep. 3:e12444 [PubMed] Schoiswohl G, Stefanovic-Racic M, Menke MN, Wills RC, Surlow BA, Basantani MK, Sitnick MT, Cai L, Yazbeck CF, Stolz DB, Pulinilkunnil T, O'Doherty RM, Kershaw EE., (2015) Impact of Reduced ATGL-Mediated Adipocyte Lipolysis on Obesity-Associated Insulin Resistance and Inflammation in Male Mice. Endocrinology. 156:3610-3624 [PubMed] Kraus D, Yang Q, Kong D, Banks AS, Zhang L, Rodgers JT, Pirinen E, Pulinilkunnil TC, Gong F, Wang YC, Cen Y, Sauve AA, Asara JM, Peroni OD, Monia BP, Bhanot S, Alhonen L, Puigserver P, Kahn BB., (2014) Nicotinamide N-methyltransferase knockdown protects against diet-induced obesity Nature 00:00 [PubMed] Zordoky BN, Nagendran J, Pulinilkunnil T, Kienesberger PC, Masson G, Waller TJ, Kemp BE, Steinberg GR, Dyck JR., (2014) AMPK-dependent inhibitory phosphorylation of ACC is not essential for maintaining myocardial fatty acid oxidation. Circ Res. 115:518-524 [PubMed] O'Neill HM, Lally JS, Galic S, Thomas M, Azizi PD, Fullerton MD, Smith BK, Pulinilkunnil T, Chen Z, Samaan MC, Jorgensen SB, Dyck JR, Holloway GP, Hawke TJ, van Denderen BJ, Kemp BE, Steinberg GR., (2014) AMPK phosphorylation of ACC2 is required for skeletal muscle fatty acid oxidation and insulin sensitivity in mice. Diabetologia :1693-702 [PubMed] Adisesh A, Melville S, Pulinilkunnil T, Lutchmedial S, Brunt KR., (2014) Holiday reading. Diving into the ice bucket challenge. CMAJ 186:1404-5 [PubMed] Pulinilkunnil T, Kienesberger PC, Nagendran J, Waller TJ, Young ME, Kershaw EE, Korbutt G, Haemmerle G, Zechner R, Dyck JR., (2013) Myocardial Adipose Triglyceride Lipase Overexpression Protects Diabetic Mice From the Development of Lipotoxic Cardiomyopathy. Diabetes. 62(5):1464-77 [PubMed] Kienesberger PC, Pulinilkunnil T, Nagendran J, Dyck JR., (2013) Myocardial triacylglycerol metabolism. J Mol Cell Cardiol. 55:101-10. [PubMed] Nagendran J, Kienesberger PC, Pulinilkunnil T, Zordoky BN, Sung MM, Kim T, Young ME, Dyck JR., (2013) Cardiomyocyte specific adipose triglyceride lipase overexpression prevents doxorubicin induced cardiac dysfunction in female mice Heart 99:1041-47 [PubMed] Kienesberger PC, Pulinilkunnil T, Nagendran J, Young ME, Bogner-Strauss JG, Hackl H, Khadour R, Heydari E, Haemmerle G, Zechner R, Kershaw EE, Dyck JR, (2013) Early structural and metabolic cardiac remodelling in response to inducible adipose triglyceride lipase ablation Cardiovasc Res. 99:442-51 [PubMed] Pulinilkunnil T, Kienesberger PC, Nagendran J, Sharma N, Young ME, Dyck JR., (2013) Cardiac-specific adipose triglyceride lipase overexpression protects from cardiac steatosis and dilated cardiomyopathy following diet-induced obesity. Int J Obes (Lond). in press.: [PubMed] Fullerton MD, Galic S, Marcinko K, Sikkema S, Pulinilkunnil T, Chen ZP, O'Neill HM, Ford RJ, Palanivel R, O'Brien M, Hardie DG, Macaulay SL, Schertzer JD, Dyck JR, van Denderen BJ, Kemp BE, Steinberg GR., (2013) Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin. Nat Med : [PubMed] Sitnick MT, Basantani MK, Cai L, Schoiswohl G, Yazbeck CF, Distefano G, Ritov V, DeLany JP, Schreiber R, Stolz DB, Gardner NP, Kienesberger PC, Pulinilkunnil T, Zechner R, Goodpaster BH, Coen P, Kershaw EE., (2013) Skeletal muscle triacylglycerol hydrolysis does not influence metabolic complications of obesity. Diabetes 62:3350-61 [PubMed] Nagendran J, Pulinilkunnil T, Kienesberger PC, Sung MM, Fung D, Febbraio M, Dyck JR., (2013) Cardiomyocyte-specific ablation of CD36 improves post-ischemic functional recovery. J Mol Cell Cardiol. 63:180-88 [PubMed] Willis MS, Bevilacqua A, Pulinilkunnil T, Kienesberger P, Tannu M, Patterson C, (2013) The role of ubiquitin ligases in cardiac disease J Mol Cell Cardiol 00:00 [PubMed] Nagendran J, Pulinilkunnil T, Kienesberger PC, Sung MM, Fung D, Febbraio M, Dyck JR, (2013) Cardiomyocyte-specific ablation of CD36 improves post-ischemic functional recovery J Mol Cell Cardiol 63:180-188 [PubMed]