The long-term goals of Veronique A. Lacombe, DVM, PhD are to become an independent, academic investigator, and to conduct cutting-edge translational research in comparative medicine, to better serve the health and welfare of both animals and humans. She is board-certified by the American College of Veterinary Internal Medicine, and received her postdoctoral research training in comparative physiology. This SERCA award will capitalize on her strong dual training in basic and clinical sciences, and is designed to foster her development toward achieving her career goals. An interdisciplinary mentoring team will provide the applicant with an intensive collaborative research experience in the rich intellectual environment of The Ohio State University. The sponsor is Sandor Gyorke, PhD, an internationally renowned leader in cardiac calcium metabolism; and the co-sponsor is Cynthia Carnes, PharmD, PhD, a uniquely qualified translational scientist in cardiovascular diseases. The applicant's research goals are to better understand the pathogenesis of diabetes, and to study interactions between cardiac metabolism and physiologic function. Diabetes has reached epidemic levels and heart failure is the cause of death in 2/3 of diabetic patients. Abnormalities in calcium (Ca) regulation in the myocardium underlie the pathologic contractile changes during cardiomyopathy and heart failure. Furthermore, during diabetes, the mechanisms of abnormal glucose transport in the myocardium are not well understood. In particular, Ca regulation of glucose transport is not well elucidated in insulin-sensitive tissues and is not defined during diabetes. The central hypothesis of this proposal is that altered intracellular Ca homeostasis which develops during diabetic cardiomyopathy, contributes to impaired glucose transport in the diabetic heart.
Our aims are to: 1) characterize the impaired cardiac function (in vivo) and Ca homeostasis (in vitro) in the diabetic myocardium; 2) to study the effects of in vitro Ca stimulation on glucose transport in normal and diabetic cardiac myocytes; 3) to test the hypothesis that treatment with a Ca channel blocker will improve intracellular Ca homeostasis and thus cardiac contractility in the diabetic myocardium; and 4) to test the hypothesis that improved Ca homeostasis (following Ca channel blocker treatment) will increase glucose transport in the diabetic myocardium. This proposal provides a unique and multidisciplinary training opportunity that will allow the candidate to enhance her skills in translational physiology, and acquire additional expertise in electrophysiology, molecular biology, and state-of-the-art in vivo and in vitro imaging techniques.
Diabetes, a widespread health problem, results in high blood sugar and is known to increase the risk of early heart disease and death. However, there is no real cure. Thus, better understanding of glucose transport in the heart could provide novel insights into heart disease, and new therapies to improve heart function during diabetes.
|Waller, Amanda P; Kalyanasundaram, Anuradha; Hayes, Summer et al. (2015) Sarcoplasmic reticulum Ca2+ ATPase pump is a major regulator of glucose transport in the healthy and diabetic heart. Biochim Biophys Acta 1852:873-81|
|Lacombe, Véronique A (2014) Expression and regulation of facilitative glucose transporters in equine insulin-sensitive tissue: from physiology to pathology. ISRN Vet Sci 2014:409547|
|Kalyanasundaram, Anuradha; Lacombe, Véronique A; Belevych, Andriy E et al. (2013) Up-regulation of sarcoplasmic reticulum Ca(2+) uptake leads to cardiac hypertrophy, contractile dysfunction and early mortality in mice deficient in CASQ2. Cardiovasc Res 98:297-306|
|Waller, Amanda P; George, Michael; Kalyanasundaram, Anuradha et al. (2013) GLUT12 functions as a basal and insulin-independent glucose transporter in the heart. Biochim Biophys Acta 1832:121-7|
|Waller, A P; Huettner, L; Kohler, K et al. (2012) Novel link between inflammation and impaired glucose transport during equine insulin resistance. Vet Immunol Immunopathol 149:208-15|
|Waller, A P; Kohler, K; Burns, T A et al. (2011) Naturally occurring compensated insulin resistance selectively alters glucose transporters in visceral and subcutaneous adipose tissues without change in AS160 activation. Biochim Biophys Acta 1812:1098-103|
|Waller, A P; Burns, T A; Mudge, M C et al. (2011) Insulin resistance selectively alters cell-surface glucose transporters but not their total protein expression in equine skeletal muscle. J Vet Intern Med 25:315-21|
|Ware, Bruce; Bevier, Marie; Nishijima, Yoshinori et al. (2011) Chronic heart failure selectively induces regional heterogeneity of insulin-responsive glucose transporters. Am J Physiol Regul Integr Comp Physiol 301:R1300-6|