| Biography: Dr. Bernier received his Ph.D. from the University of Montreal, Canada, in 1983, and completed two postdoctoral fellowships. The first one was held at INSERM U.162 in Lyon, France, and the second one at the Johns Hopkins University School of Medicine in Baltimore. He was an assistant professor of Biochemistry at McGill University in Canada before joining the NIA in 1990. He became a Tenure-Track Investigator in July 1994. His current projects include investigation of the molecular aspects of insulin receptor signal transduction. He is a member of the American Diabetes Association and the Endocrine Society. |
| Research Overview: The central theme of the research in my laboratory involves the use of molecular biology and biochemistry to study the mechanism whereby the signal generated by the insulin binding to its cell surface receptor is transmitted intracellularly to various enzymes and proteins. Our objectives are to dissect the signaling networks, specific functional complexes, and molecular mechanisms that underlie the regulation of mitogenesis and metabolism by insulin. Specifically, the laboratory is actively engaged in (a) understanding structure/function relationships of the insulin receptor and two newly-described interacting proteins, namely the actin-binding protein, filamin A, and phospholipase C-gamma1 (PLCg1); (b) assessing the contributions of these interactions to insulin signaling in insulin-responsive cells (e.g., hepatocytes, adipocytes); and (c) applying the gained knowledge to devise strategies to interfere with aberrant mechanisms in insulin signal transduction seen in patients with obesity, type II diabetes and aging. |
| We have recently identifed filamin A and PLCg1 as genuine partners of the insulin receptor in cultured cell lines and in a primary culture of rat hepatocytes, which reflects the potential for physiological significance. Filamin A and PLCg1 possess discrete domains that allow their binding with the insulin receptor. A mechanistic understanding of the regulation of these specific functional complexes could ultimately be used for the design of novel approaches to control the activity and/or intracellular redistribution of these signaling molecules in various insulin resistance states. In addition, using mutational techniques, we are mapping a functional domain of the insulin receptor involved in receptor-mediated PLCg1 interaction and in coupling of the activated receptor to downstream signal transduction molecules. Finally, we are studying the role of PLCg1 and filamin A in adipocyte differentiation and as modulators of insulin-stimulated metabolic responses in hepatocytes and adipocytes. |
| Current studies are using multiple methods (antibody arrays, DNA arrays, proteomic technologies) to identify candidate genes that are up- or down-regulated in cells expressing filamin A or PLCg1 constructs versus control hepatocytes or adipocytes following exposure to insulin. The pathways regulating these candidate genes will then be studied in detail. Obesity-linked insulin resistance and changes associated with aging have been linked to proinflammatory cytokine signaling. New efforts within the laboratory include research activities to dissect related signaling mechanisms in the control of proinflammatory responses in freshly isolated human T-lymphocytes. We have recently been involved in a collaborative effort to elucidate unexplored mechanisms in the regulation of cytokine signaling by short-lived farnesylated proteins. This information may provide perspectives for new strategies to improve insulin resistance. |
| Recent Publications: |
- Kwon YK, Jang HJ, Kole S, He HJ, Bernier M. Role of the pleckstrin homology domain of PLCg1 in its interaction with the insulin receptor. J. Cell Biol. 163(2): 375-384, 2003.
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- He HJ, Kole S, Kwon YK, Crow MT, Bernier M. Interaction of filamin A with the insulin receptor alters insulin-dependent activation of the mitogen-activated protein kinase pathway. J. Biol. Chem. 278(29): 27096-27104, 2003.
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- Doyle ME, Theodorakis MJ, Holloway HW, Bernier M, Greig NH, Egan JM. The importance of the nine-amino acid C-terminal sequence of exendin-4 for binding to the GLP-1 receptor and for biological activity. Regul. Pept. 114(2-3): 153-158, 2003.
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- Pandey SK, He HJ, Chesley A, Juhaszova M, Crow MT, Bernier M. Wortmannin-sensitive pathway is required for insulin-stimulated phosphorylation of inhibitor kBa. Endocrinology. 143(2): 375-385, 2002.
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