Unexpected Consequences of Insulin Resistance for the Heart

描述(由申请人提供)：我目前的目标是获得必要的技能和专业知识，以便在基础心血管研究的学术领域成功过渡到独立。这项工作的长期目标是促进我们对控制心脏中葡萄糖和脂肪酸利用的分子机制的了解。过早死亡和心血管疾病致残是糖尿病的可怕并发症。糖尿病与高循环水平的葡萄糖和脂肪酸有关，这两种物质都是为心脏提供能量的底物。像有机体中其他对胰岛素有反应的组织一样，糖尿病患者的心脏也会出现胰岛素抵抗。由于对胰岛素反应的葡萄糖摄取受损是心肌胰岛素抵抗(MIR)的主要特征，我认为MIR是心脏保护自身免受糖尿病高血糖环境影响的适应性计划的一部分。其理论基础来自于观察到，增加对心脏的葡萄糖供应导致葡萄糖摄取率高于葡萄糖氧化速率，即细胞内葡萄糖氧化速率 葡萄糖中间体的积聚，以及随后的收缩功能障碍。特异靶1将确定高血糖对心脏基因表达的影响。这一目标将检验这样一种假设，即心脏内葡萄糖代谢产物的细胞内积累重新激活了胎儿基因程序，这可以通过胰岛素介导的葡萄糖摄取受损来防止。具体目标2将确定MIR对慢性压力超负荷下心脏能量代谢和收缩功能的影响。具体地说，它将检验这样一种假设，即MIR在限制葡萄糖摄取的同时增加葡萄糖氧化，并延迟应激心脏向衰竭的转变。特殊目标3将寻求识别分子 在应激心脏中控制底物选择的机制。它将检验解偶联蛋白3(UCP3)通过抑制葡萄糖氧化而降低高工作负荷下心脏效率的假设。这些目标将通过将我在分子生物学方面的经验与导师实验室中可用的技术相结合来实现，并将为未来旨在确定胰岛素信号和UCP3在心脏中表达之间的联系的研究奠定基础。总而言之，这项拟议的工作试图证明，MIR更多地是糖尿病患者应激心脏的一种生理反应，而不是心力衰竭的主要原因。

DESCRIPTION (provided by applicant): My immediate goal is to acquire the necessary skills and expertise to make a successful transition to independence in the academic field of basic cardiovascular research. The long term goals of this work are to advance our knowledge on the molecular mechanisms that control glucose and fatty acid utilization in the heart. Premature death and disability from cardiovascular diseases are dire complications in diabetes. Diabetes is associated with high circulating levels of glucose and fatty acids, which are both energy providing substrates for the heart. Like other insulin-responsive tissues in the organism, the heart in diabetes becomes insulin resistant. Because impaired glucose uptake in response to insulin is the main feature of myocardial insulin resistance (MIR), I propose that MIR is part of an adaptive program with which the heart protects itself from the hyperglycemic milieu of diabetes mellitus. The rationale arises from the observation that increased glucose supply to the heart results in rates of glucose uptake greater than rates of glucose oxidation, the intracellular accumulation of glucose intermediates and, subsequently, contractile dysfunction. Specific Aim 1 will determine the effects of hyperglycemia on cardiac gene expression. This aim will test the hypothesis that the intracellular accumulation of glucose metabolites in the heart reactivates the fetal gene program, which can be prevented by the impairment of insulin-mediated glucose uptake. Specific Aim 2 will define the effect of MIR on energy metabolism and contractile function of the heart subjected to chronic pressure overload. Specifically, it will test the hypothesis that MIR increases glucose oxidation while limiting glucose uptake, and delays the transition toward failure of the stressed heart. Specific Aim 3 will seek to identify the molecular mechanism controlling substrate selection in the stressed heart. It will test the hypothesis that the uncoupling protein 3 (UCP3) decreases efficiency of the heart subjected to a high workload by inhibiting glucose oxidation. These aims will be addressed by combining my experience in molecular biology to the techniques available in the mentor's laboratory, and will set the path to future investigations aiming to define the links between insulin signaling and the expression of UCP3 in the heart. Collectively, the proposed work seeks to demonstrate that MIR is more a physiological response for the stressed heart in diabetes, rather than a primary cause for heart failure.