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

糖尿病期间心肌葡萄糖转运受损：钙的新作用

• 批准号: 8138358
• 负责人: VERONIQUE A LACOMBE
• 金额: $ 5.54万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-24 至 2012-01-27
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8138358
• 关键词: Action Potentials; Active Sites; Adipocytes; Age; American; Animals; Award; Back; Basic Science; Blood Glucose; Ca(2+)-Transporting ATPase; Calcium; Calcium Channel Blockers; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiovascular Diseases; Cause of Death; Cell surface; Cells; Cessation of life; Clinical Sciences; Comparative Physiology; Control Groups; Defect; Development; Diabetes Mellitus; Diltiazem; Doctor of Pharmacy; Doctor of Philosophy; Electrophysiology (science); Environment; Epidemic; Fostering; Frequencies; Functional disorder; GLUT4 gene; Glucose; Glucose Transporter; Goals; Health; Heart; Heart Diseases; Heart failure; Homeostasis; Human; Imaging Techniques; In Vitro; Insulin; Internal Medicine; Measurement; Measures; Medicine; Mentors; Molecular Biology; Muscle Cells; Myocardial; Myocardium; Ohio; Pathogenesis; Pathologic; Physiological; Physiology; Placebos; Pump; Qualifying; Rattus; Regulation; Relaxation; Research; Research Personnel; Research Training; Risk; Role; RyR2; Ryanodine Receptor Calcium Release Channel; SERCA2a; Sarcoplasmic Reticulum; Scientist; Skeletal Muscle; Social Welfare; Techniques; Testing; Tissues; Training; Translational Research; Universities; Ventricular; Vesicle; Western World; calcium metabolism; career; channel blockers; college; comparative; design; diabetic; diabetic cardiomyopathy; diabetic patient; diabetic rat; experience; glucose metabolism; glucose transport; glucose uptake; heart function; heart metabolism; improved; in vivo; insight; multidisciplinary; novel; novel therapeutics; phospholamban; programs; protein expression; reuptake; skills; trafficking; uptake

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.

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前沿的转化研究，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医学院的委员会认证，并接受了比较生理学的博士后研究培训。该 SERCA 奖项将利用她在基础科学和临床科学方面强大的双重培训，旨在促进她实现职业目标的发展。跨学科的指导团队将为申请人在俄亥俄州立大学丰富的智力环境中提供深入的合作研究经验。发起人为国际知名心脏钙代谢领域领军人物Sandor Gyorke博士；共同发起人是辛西娅·卡恩斯 (Cynthia Carnes)，她是药学博士、哲学博士，是一位心血管疾病领域具有独特资格的转化科学家。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。糖尿病已达到流行程度，心力衰竭是2/3糖尿病患者的死亡原因。心肌钙 (Ca) 调节异常是心肌病和心力衰竭期间病理性收缩变化的基础。此外，在糖尿病期间，心肌中葡萄糖转运异常的机制尚不清楚。特别是，Ca 对葡萄糖转运的调节在胰岛素敏感组织中尚未得到很好的阐明，并且在糖尿病期间也没有被定义。该提议的中心假设是，糖尿病心肌病期间发生的细胞内 Ca 稳态改变，导致糖尿病心脏中的葡萄糖转运受损。我们的目标是：1）表征糖尿病心肌中受损的心功能（体内）和 Ca 稳态（体外）； 2）研究体外Ca刺激对正常和糖尿病心肌细胞葡萄糖转运的影响； 3) 检验 Ca 通道阻滞剂治疗将改善细胞内 Ca 稳态，从而改善糖尿病心肌的心肌收缩力的假设； 4) 检验改善 Ca 稳态（在 Ca 通道阻滞剂治疗后）将增加糖尿病心肌中葡萄糖转运的假设。该提案提供了独特的多学科培训机会，使候选人能够提高转化生理学方面的技能，并获得电生理学、分子生物学以及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，更好地了解心脏中的葡萄糖转运可以为心脏病提供新的见解，并提供改善糖尿病期间心脏功能的新疗法。