HuR as a Regulator of Skeletal Muscle Metabolism

项目总结/摘要 基于代谢底物的可用性、代谢灵活性在代谢底物之间切换的能力需要一个 分子相互作用的复杂网络，以实现有效功能。我们发现这个网络的一方面 是HuR对mRNA转录水平的控制。HuR是一种RNA结合蛋白， 转录物及其在细胞内的翻译。尽管HuR已经被广泛研究了它在 增殖、炎症和凋亡，其作为代谢传感器的作用相对未知。我们 初步数据表明，骨骼肌特异性HuR敲除小鼠显示出增加的胰岛素抗性， 和肥胖症。有趣的是，这些小鼠显示出增加的HuR靶标水平， 转录本，同时也显示这些转录本的翻译蛋白水平降低。不良代谢 骨骼肌中HuR下调导致的预后也补充了我们收集的数据 用于代谢不健康的男性和女性人类骨骼肌样品。拟议的目标将 因此，测试HuR靶转录物向核糖体的递送促进代谢的假设， 通过影响mTOR信号通路来提高灵活性。 非常重要的是，Warfel博士将学习新的方法技术，以发展他的职业生涯， 一位专注于RNA生物学和代谢的独立研究者。本提案中的方法包括 转基因小鼠模型的产生和表型分析，代谢室和放射性代谢物的使用 分析、生物信息学和分子生物学。这些技术的培训也将提供初步的 这些数据是开发未来项目所必需的，这些项目旨在了解RNA结合蛋白对 细胞代谢稳态，并考虑治疗胰岛素抵抗的新的潜在途径 和肥胖。这是Warfel博士长期的研究期望，他组建了一支杰出的团队 在与本提案相关的领域具有丰富经验的导师和合作者，他们将提供 指导以确保Warfel博士实现独立。

PROJECT SUMMARY/ABSTRACT The ability to switch between metabolic substrates based on their availability, metabolic flexibility, requires a complex network of molecular interactions for efficient function. We have found that one aspect of this network is the control of mRNA transcript levels by HuR. HuR is an RNA-binding protein that regulates levels of RNA transcripts and their translation within cells. Though HuR has been extensively studied for its roles in proliferation, inflammation, and apoptosis, its action as a metabolic sensor is relatively unknown. Our preliminary data indicate that skeletal muscle specific HuR knockout mice show increased insulin resistance and adiposity relative to control animals. Interestingly, these mice show increased levels of HuR target transcripts, while also showing decreased translated protein levels for these transcripts. The poor metabolic prognosis resulting from down regulation of HuR in skeletal muscle also complements data we have collected for metabolically unhealthy male and female human skeletal muscle samples. The proposed aims will therefore test the hypothesis that delivery of HuR target transcripts to the ribosome promotes metabolic flexibility by influencing the mTOR signaling pathway. Very important is the new methodological techniques that Dr. Warfel will learn in order to develop his career as an independent investigator focused on RNA biology and metabolism. Methods in this proposal include transgenic mouse model generation and phenotyping, use of metabolic chambers and radioactive metabolite assays, bioinformatics and molecular biology. The training in these techniques will also provide the preliminary data necessary to develop future projects aimed at understanding the contribution of RNA binding proteins to cellular metabolic homeostasis, and to consider new potential avenues in the treatment of insulin resistance and obesity. This is Dr. Warfel’s long-term research expectation, and he has assembled an outstanding team of mentors and collaborators with extensive experience in areas relevant to this proposal who will provide guidance to ensure that Dr. Warfel achieves independence.