Self-Renewal of the Cardiomyocyte

描述（由申请人提供）：我们对心脏萎缩性重塑的研究使我们认识到一个简单的生物学原理：从细胞周期到克雷布斯周期，没有周期就没有生命。虽然细胞再生的潜力受到了很多关注，但细胞内蛋白质周转的动力学只得到了选择性的考虑。虽然“身体成分的动态状态”的概念自20世纪40年代以来就存在，但心肌细胞从内部自我更新的想法相对较新。在过去的30年里，我们（和许多其他人）已经阐明了能量供应和心脏收缩的代谢途径的相互作用。该领域的工作已经发现了新的酶作用的代谢调节剂，但心肌能量代谢对心肌蛋白质周转的影响从未被考虑过。我们现在提出，代谢信号是心肌蛋白质合成和降解的假定调节因子。从广义上讲，我们试图建立完整心肌细胞自我更新的机制。基本原理是基于我们的观察，即心脏的萎缩性重塑同时激活细胞内蛋白质合成和降解的途径。具体目标1将确定代谢信号如何调节蛋白质降解。它将测试的假设，有一个中间代谢和蛋白质降解之间的直接联系，具体的分子机制涉及泛素连接酶的AMPK调节。具体目标2将确定蛋白质合成的代谢信号。它将检验以下假设：中间代谢和蛋白质合成之间也存在直接联系，碳水化合物调节mTOR，并且特定的分子机制涉及G6P对TSC 2的调节。具体目标3将确定营养胁迫如何影响代谢信号和蛋白质周转。这一目标将检验以下假设：当营养物质过量时，葡萄糖摄取受损（IGU）会影响蛋白质周转，并且IGU会保护心脏免受压力过载引起的非稳态代谢应激。总的来说，拟议的工作旨在确定代谢信号作为心肌蛋白质周转的调节剂，并寻求扩大能量底物代谢的作用，从ATP的提供者到心肌细胞自我更新的调节剂。

DESCRIPTION (provided by applicant): Our work on atrophic remodeling of the heart has caused us to appreciate a simple principle in biology: From the cell cycle to the Krebs cycle there is no life without cycles. While the potential for cellular regeneration receives much attention, the dynamics of intracellular protein turnover have received only selective consideration. Although the concept of the "dynamic state of body constituents" exists since the 1940s, the idea that heart muscle cells renew themselves from within is relatively new. For the last 30 years we (and many others) have elucidated the interaction of metabolic pathways for energy provision and contraction of the heart. Work in the field has uncovered novel metabolic regulators of enzyme action, yet the impact of myocardial energy metabolism on myocardial protein turnover has never been considered. We now propose that metabolic signals are putative regulators of myocardial protein synthesis and degradation. In a broad sense, we seek to establish mechanisms underlying the self-renewal of intact cardiomyocytes. The rationale is based on our observation that atrophic remodeling of the heart simultaneously activates pathways of intracellular protein synthesis and degradation. Specific Aim 1 will determine how metabolic signals regulate protein degradation. It will test the hypothesis that there is a direct link between intermediary metabolism and protein degradation and that the specific molecular mechanisms involve AMPK regulation of ubiquitin ligases. Specific Aim 2 will identify metabolic signals of protein synthesis. It will test the hypothesis that a direct link also exists between intermediary metabolism and protein synthesis, that carbohydrates regulate mTOR, and that the specific molecular mechanisms involve G6P regulation of TSC2. Specific Aim 3 will determine how nutrient stress affects metabolic signals and protein turnover. This aim will test the hypothesis that impaired glucose uptake (IGU) affects protein turnover when nutrients are over abundant, and that IGU protects the heart from allostatic metabolic stress in response to pressure overload. Collectively, the proposed work seeks to identify metabolic signals as regulators of myocardial protein turnover and seeks to broaden the role energy substrate metabolism from a provider of ATP to a regulator of self-renewal of the cardiomyocyte.