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)的治疗效果很差。为了开发新的特效疗法，有必要更多地了解导致这种疾病的有害机制。这项研究的重点是测试针对不良适应机制的治疗方法，这些机制将改善心力衰竭受损的收缩能力和不足的能量产生。我们的长期目标是确定新的高度特异的治疗靶点来治疗心力衰竭。我们的近期目标是确定减少过量的蛋白质OGlcN酰化到正常是否可以改善心衰患者的心功能。我们的初步结果表明，在HF核中，胞浆、肌浆网(SR)和线粒体(MITO)的心肌蛋白过度OGlcN酰化。此外，通过转基因表达减少心力衰竭小鼠的O-GlcN酰化可改善心功能。假说是心衰引起的心肌细胞1：ES(CM)异常可以通过表达特定的转基因来纠正非适应性过量蛋白OGlcNacylation和/或其对关键心肌蛋白的缺失效应。在HF小鼠模型或转基因HF小鼠中使用病毒载体基因转移应达到以下特定目标：i)确定和确定在PO诱导的HF演变过程中，导致完整CM和CM特定细胞器中蛋白质过度0-GlcN酰化的时间过程和机制。2)确定过量的CM蛋白0-GlcN酰化的减弱或逆转是否改善了衰竭心脏的功能。3)证实特定蛋白质的过量0-GlcN酰化会降低Mito功能并传播HF。在目标I中，我们探讨了导致心力衰竭中蛋白质过度0-GlcN酰化的机制，并确定了发生过度0-GlcN酰化的关键心脏蛋白质。AIM I与AIM II相关，因为在AIM II中，我们确定逆转HF CM中过多的核蛋白、胞浆蛋白和SR蛋白0-GlcN酰化是否改善CM和心功能。目的III证实，特定蛋白质过度的0-GlcN酰化会削弱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.