Self-Renewal of the Cardiomyocyte

描述(申请人提供)：我们在心脏萎缩性重塑方面的工作使我们认识到生物学中的一个简单原理：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大的关注，但细胞内蛋白质周转的动力学只受到了选择性的考虑。虽然“身体成分的动态状态”的概念早在20世纪40年代就已经存在，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(和其他许多人)阐明了代谢途径与心脏能量供应和收缩的相互作用。这一领域的工作已经发现了酶作用的新的代谢调节因子，但从未考虑过心肌能量代谢对心肌蛋白质周转的影响。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器。从广义上讲，我们试图建立完整的心肌细胞自我更新的机制。其理论基础是基于我们的观察，心脏的萎缩性重塑同时激活了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。它将检验中间代谢和蛋白质降解之间存在直接联系的假设，以及特定的分子机制涉及AMPK对泛素连接酶的调节。特定目标2将识别蛋白质合成的代谢信号。它将检验这样的假设，即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，以及特定的分子机制涉及G6P对TSC2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。这一目标将检验这样一种假设，即当营养物质过多时，葡萄糖摄取受损(IGU)会影响蛋白质的周转，并且IGU保护心脏免受因压力超负荷而产生的稳态代谢应激。总之，这项拟议的工作试图确定代谢信号是心肌蛋白质周转的调节者，并试图将能量底物代谢的作用从ATP的提供者扩大到心肌细胞自我更新的调节者。

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.