O-GlcN Acylation & Dynamin Proteins in CHF

项目总结（见说明书）：目前的治疗方法对心力衰竭（HF）的治疗效果不佳。为了开发新的特异性疗法，有必要对产生这种疾病的有害机制有更多的了解。本研究的重点是测试针对适应不良机制的治疗方法，这些机制将改善HF中受损的收缩力和能量产生不足。我们的长期目标是确定新的高度特异性的治疗靶点来治疗HF。我们的近期目标是确定将过量的蛋白质OGlcNAc化降低至正常是否可以改善HF患者的心脏功能。我们的初步结果表明，在HF核，胞浆，肌浆网（SR）和线粒体（Mito）的心脏蛋白过度OGlcNAc酰化。此外，在HF小鼠中通过转基因表达减少O-GlcNAc化导致心脏功能改善。该假说认为，HF诱导的心肌细胞1：es（CM）异常可以通过特定转基因的表达来逆转，这些转基因可以纠正适应不良的过度蛋白OGlcNAc化和/或其对关键心肌蛋白的有害作用。在HF的小鼠模型或具有HF的转基因小鼠中使用病毒载体基因转移，应实现以下具体目标：i）鉴定和确定在PO诱导的HF的演变期间促成完整CM中和CM的特定细胞器中的蛋白质的过度O-GlcNAc酰化的时程和机制。2)确定过度CM蛋白0-GlcNAc化的减弱或逆转是否改善衰竭心脏的功能。3)确定特定蛋白质的过度0-GlcNAc酰化降低Mito功能并传播HF。在目的I中，探索了导致HF中蛋白质过度0-GlcNAc酰化的机制，并鉴定了经历过度0-GlcNAc酰化的关键心脏蛋白。目的I与目的II相关，因为在目的II中，我们确定HF CM中过度的核、胞质和SR蛋白0-GlcNAc化的逆转是否改善CM和心脏功能。目的III确定特定蛋白质的过度0-GlcNAc酰化降低Mito功能。

PROJECT SUMMARY (See instructions): Heart failure (HF) is poorly treated by current therapies. More knowledge of the deleterious mechanisms that produce this disease is necessary in order to develop novel specific therapies. The focus of this research is on testing therapeutic approaches targeting maladaptive mechanisms that will improve impaired contractility and deficient energy production in HF. Our long-term goal is to identify new highly specific therapeutic targets to treat HF. Our immediate goals are to determine if reducing excessive protein OGlcNAcylation to normal can improve cardiac function in HF. Our preliminary results show that in HF nuclear, cytosolic, sarcoplasmic reticulum (SR) and mitochondrial (Mito) cardiac proteins are excessively OGlcNAcylated. Furthermore, reducing O-GlcNAcylation by transgene expression in mice with HF resulted in improved cardiac function. The hypothesis is that HF-induced abnormalities in cardiac myoc)1:es (CM) can be reverted by expression of specific transgenes that correct the maladaptive excessive protein OGlcNAcylation and/or its deletrious effects on key myocardial proteins. Using viral vector gene transfer in a mouse model of HF, or transgenic mice with HF the following specific goals should be achieved: i) Identify and determine the time course and mechanisms contributing to excessive 0-GlcNAcylation of proteins in the intact CM and in specific organelles of the CM during the evolution of PO-induced HF. 2) Determine if attenuation or reversal of excessive CM protein 0-GlcNAcylation improves function in the failing heart. 3) Establish that excessive 0-GlcNAcylation of specific proteins diminishes Mito function and propagates HF. In Aim I the mechanisms contributing to excessive protein 0-GlcNAcylation in HF are explored and key cardiac proteins that undergo excessive 0-GlcNAcylation are identified. Aim I is related to Aim II, in that in Aim II we determine if reversal of excessive nuclear, cytosolic and SR protein 0-GlcNAcylation in CM of HF improves CM and heart function. Aim III establishes that excessive 0-GlcNAcylation of specific proteins diminishes Mito function.