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

描述（由申请人提供）：Veronique A. Lacombe， DVM， PhD的长期目标是成为一名独立的学术研究者，并在比较医学领域进行尖端的转化研究，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院的董事会认证，并接受了比较生理学的博士后研究培训。这个SERCA奖将利用她在基础科学和临床科学方面的双重训练，旨在促进她实现职业目标的发展。跨学科的指导团队将在俄亥俄州立大学丰富的学术环境中为申请人提供密集的合作研究经验。赞助人为Sandor Gyorke博士，国际知名心脏钙代谢领域的领军人物；共同发起人是Cynthia Carnes，药学博士，她是一位非常合格的心血管疾病转化科学家。申请人的研究目标是更好地了解糖尿病的发病机制，并研究心脏代谢与生理功能之间的相互作用。糖尿病已达到流行病水平，2/3的糖尿病患者因心力衰竭而死亡。心肌钙（Ca）调节异常是心肌病和心力衰竭期间病理收缩变化的基础。此外，在糖尿病期间，心肌中异常葡萄糖转运的机制尚不清楚。特别是，钙对葡萄糖转运的调节在胰岛素敏感组织中还没有很好地阐明，在糖尿病中也没有明确定义。该建议的中心假设是糖尿病心肌病期间发生的细胞内钙稳态改变导致糖尿病心脏中葡萄糖转运受损。我们的目的是：1)表征糖尿病心肌的心功能受损（体内）和钙稳态受损（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可以改善糖尿病心肌细胞内钙稳态，从而改善心脏收缩力的假设；4)验证改善钙稳态（在钙通道阻滞剂治疗后）会增加糖尿病心肌中葡萄糖转运的假设。该提案提供了一个独特的多学科培训机会，使候选人能够提高她在转化生理学方面的技能，并获得电生理学，分子生物学和最先进的体内和体外成像技术方面的额外专业知识。相关性：糖尿病是一种普遍存在的健康问题，会导致高血糖，并增加早期心脏病和死亡的风险。然而，没有真正的治疗方法。因此，更好地了解心脏中的葡萄糖转运可以为心脏病提供新的见解，并为改善糖尿病患者的心脏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.