Integrative Calcium Biology in Diabetes and Metabolic Disease
Our laboratory is broadly interested in the biology of calcium signaling. Thousands of calcium channels on the cell’s plasma membrane precisely control the timing and entry of calcium ions. Calcium permeates the membrane of virtually every cell to mediate vital processes such as contraction, vesicle secretion, gene transcription, and programmed cell death, to name a few. Loss of Ca2+ homeostasis, most often in the form of increases in intracellular Ca2+, leads to cell injury. Depending on the cell type and the intensity of Ca2+ toxicity, the injury may be reversible or irreversible.
Lipid-mediated Ca2+ dysregulation has now emerged as a major component of diabetes. However, presently, we have little insight into the nexus of Ca2+ and lipid biology under conditions of prolonged exposure to excess lipids. Furthermore, a systematic analysis of Ca2+ responses to different species of lipids across different cell types has not been performed. Finally, while we, and many others, have performed lipid profiling of patient sera to demonstrate that saturated fatty acids are associated with risk for diabetes and metabolic disease, whereas unsaturated fatty acids are potentially protective, little molecular, mechanistic insight has been gained as to the contribution of these fatty acids to lipotoxicity. In the Greka laboratory, we have developed a new research platform called Calcilipidomics, a highly innovative yet carefully designed approach to the comprehensive analysis of lipid and Ca2+ signaling across a wide spectrum of cell types involved in metabolic diseases.
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2. Carrasquillo R, Tian D, Krishna S, Pollak MR, Greka A*, Schlöndorff J*. SNF8, a member of the ESCRT-II complex, interacts with TRPC6 and enhances its channel activity. BMC Cell Biol.13:33, Free PMC Article * co-corresponding authors
3. Greka, A and Mundel, P. Regulation of podocyte actin dynamics by calcium. Semin. Nephrol. 32(4): 319-26, 2012. PMCID: PMC3581337
4. Greka, A and Mundel, P. Cell biology and pathology of the podocyte. Annual Reviews of Physiology 74: 299-323, PMCID: PMC3600372
5. Greka, A and Mundel, P. Balancing calcium signals through TRPC5 and TRPC6 in podocytes. Journal of the American Society of Nephrology 22: 1969-1980, 2011.
6. Tian, D., Jacobo, S.M., Billing, D., Rozkalne, A., Gage, S.D., Anagnostou, T., Pavenstadt, H., Hsu, H., Schlöndorff, J., Ramos, A., and Greka, A. Antagonistic regulation of actin dynamics and cell motility by TRPC5 and TRPC6 channels, Science Signaling 3, ra77, 2010. PMCID: PMC3071756
7. Rhee, EP, Souza, A, Farell, L., Steele, JRD, Pollak, M, Thadhani, R, Clish, CB, Greka, A and Gerszten, RE. Metabolite Profiling Identifies Novel Markers of Uremia and the Hemodialysis Procedure, J Am Soc Nephrol. 2010 June; 21(6): 1041–2051. PMCID: PMC2900954