Membrane-Mediated Alterations in Diabetes

描述（由申请人提供）：糖尿病性心肌病是一种复杂的疾病，由糖尿病状态下心脏脂质代谢的不适应变化引起。长期且几乎完全依赖脂肪酸底物来促进心肌收缩功能，最终导致明显的代谢性肌病，其临床特征是舒张功能障碍、心室肥厚和生物能量低下，这些共同增加了糖尿病患者的发病率和死亡率。糖尿病患者不仅易患糖尿病状态的侵袭性血管动脉粥样硬化，而且易患心肌缺血对代谢受损心肌的不良影响。该项目的统一假设是，在糖尿病心肌中，脂肪酸底物的过度利用以葡萄糖为代价来促进血液动力学功能，导致代谢失衡，导致磷脂酶的适当激活，从而导致膜功能障碍。这些膜功能的改变损害了糖尿病心肌的生物能量效率和代谢灵活性，并导致糖尿病心肌对缺血性损伤的易感性增加。长期过量使用脂肪酸会导致有毒脂质代谢物的积累，如酰基辅酶a，它在心脏生物能量学和心肌细胞信号传导中起双重作用。酰基辅酶a的积累导致细胞内钙非依赖性磷脂酶（iPLA2s）的激活（项目1），从而损害膜功能，并通过改变心磷脂含量和分子种类组成导致线粒体生物能量效率的改变（项目2）。此外，长期和过度利用CD36来促进脂肪酸的运输和运输最终导致CD36信号功能的功能失调改变（项目3）。这种扭曲是通过糖尿病心肌中胰岛素信号的慢性减少而传播的，导致Akt信号的减少（Project 4），这对心肌有多种影响，包括FOXO1磷酸化的减少，阻止胰岛素介导的CD36转录和翻译的生理性抑制。糖尿病状态下磷脂酶和CD36的长期激活改变了糖尿病心肌的膜功能、脂肪酸运输和运输，从而传播代谢性肌病和改变细胞信号。最终，线粒体功能障碍导致有效氧化脂质能力下降，促进心功能障碍的前馈循环。拟议的研究扩展了原计划研究者的发现，这些发现是糖尿病状态的生化和病理后遗症的基础。该计划提供了一个高度协同和互动的基础，通过集成的科学主题的组成项目，有效地与脂质组学，蛋白质组学的使能技术接口。心肌功能的代谢组学和多参数生理评估。

DESCRIPTION (provided by applicant): Diabetic cardiomyopathy is a complex disorder that results from maladaptive changes in cardiac lipid metabolism in the diabetic state. The prolonged and nearly exclusive reliance on fatty acid substrate to fuel contractile function in myocardium ultimately leads to an overt metabolic myopathy that is characterized clinically by the presence of diastolic dysfunction, ventricular hypertrophy and bioenergetic inefficiency that collectively increase the morbidity and mortality in diabetic patients. Diabetic patients are subject not only to the aggressive vascular atherosclerosis characteristic of the diabetic state, but are also predisposed to the increased adverse effects of myocardial ischemia on metabolically compromised myocardium. The unifying hypothesis of the program project is that the excessive utilization of fatty acid substrate to fuel hemodynamic function at the expense of glucose in diabetic myocardium results in a metabolic imbalance that leads to the in appropriate activation of phospholipases precipitating membrane dysfunction. These alterations in membrane function compromise the bioenergetic efficiency and metabolic flexibility of diabetic myocardium and result in the increased susceptibility of diabetic myocardium to ischemic damage. The chronic excessive use of fatty acids results in the accumulation of toxic lipid metabolites such as acyl-CoA that serve dual roles in both cardiac bioenergetics and in cardiac myocyte signaling. Accumulation of acyl-CoA leads to the activation of intracellular calcium independent phospholipases (iPLA2s) (Project 1) that compromise membrane function and lead to alterations in mitochondrial bioenergetic efficiency through changes in cardiolipin content and molecular species composition (Project 2). Moreover, the chronic and excessive utilization of CD36 to facilitate fatty acid transport and trafficking ultimately leads to dysfunctional changes in CD36 signaling functions (Project 3). This distortion is propagated by chronic decreased insulin signaling in diabetic myocardium leading to decreased Akt signaling (Project 4) that has multiple effects on myocardium including the decreased phosphorylation of FOXO1 preventing physiologic insulin-mediated suppression of CD36 transcription and translation. The prolonged activation of phospholipases and CD36 in the diabetic state alters membrane function, fatty acid transport and trafficking that propagates the metabolic myopathy and altered cellular signaling in diabetic myocardium. Ultimately, mitochondrial dysfunction leads to a decrease in the ability to oxidize lipids efficiently promoting a feed forward cycle of cardiac dysfunction. The proposed research extends original discoveries made by Program investigators that are fundamental to the biochemical and pathologic sequelae of the diabetic state. The program provides a highly synergistic and interactive foundation through the integrated scientific themes of the component projects that are efficiently interfaced with the enabling technologies of lipidomics, proteomics. metabolomics and multiparametric physiologic assessments of myocardial function.