Impaired myocardial glucose transport during diabetes: the novel role of calcium

描述(申请人提供)：Veronique A.Lacombe博士的长期目标是成为一名独立的学术研究人员，并在比较医学领域开展尖端的翻译研究，以更好地服务于动物和人类的健康和福利。她获得了美国兽医内科学会的董事会认证，并接受了比较生理学的博士后研究培训。这一SERCA奖项将利用她在基础和临床科学方面的强大双重培训，旨在促进她朝着实现职业目标的方向发展。一个跨学科的指导团队将在俄亥俄州立大学丰富的智力环境中为申请者提供密集的协作研究经验。赞助商是心脏钙代谢领域的国际知名领先者Sandor Gyorke博士，共同赞助人是心血管疾病领域唯一有资质的翻译科学家辛西娅·卡恩斯。申请者的研究目标是更好地了解糖尿病的发病机制，并研究心脏代谢和生理功能之间的相互作用。糖尿病已经达到流行水平，心力衰竭是三分之二的糖尿病患者的死亡原因。心肌钙调节异常是心肌病和心力衰竭病理性收缩变化的基础。此外，在糖尿病期间，心肌中葡萄糖异常转运的机制还不是很清楚。特别是，钙对葡萄糖运输的调节在胰岛素敏感的组织中没有得到很好的阐明，在糖尿病期间也没有定义。这一建议的中心假设是，在糖尿病心肌病期间发生的细胞内钙稳态的改变，有助于糖尿病心脏中葡萄糖运输的受损。我们的目标是：1)表征糖尿病心肌中受损的心功能(体内)和钙稳态(体外)；2)研究体外钙刺激对正常和糖尿病心肌细胞葡萄糖转运的影响；3)验证钙通道阻滞剂治疗将改善糖尿病心肌细胞内钙稳态从而改善心肌收缩能力的假说；以及4)测试改善钙稳态(钙通道阻滞剂治疗后)将增加糖尿病心肌葡萄糖转运的假说。这项建议提供了一个独特的多学科培训机会，使应聘者能够提高她在翻译生理学方面的技能，并获得更多电生理学、分子生物学和最先进的体内和体外成像技术方面的专业知识。相关性：糖尿病是一种普遍的健康问题，会导致高血糖，并已知会增加早期心脏病和死亡的风险。然而，没有真正的治愈方法。因此，更好地了解葡萄糖在心脏中的运输可以为心脏病提供新的见解，并为改善糖尿病期间的心功能提供新的治疗方法。

DESCRIPTION (provided by applicant): 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. RELEVANCE: 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.