HuR as a Regulator of Skeletal Muscle Metabolism

项目摘要/摘要 根据代谢底物的可用性和代谢灵活性在代谢底物之间切换的能力需要 分子相互作用的复杂网络，实现高效的功能。我们发现这个网络的一个方面 是HUR对mRNA转录水平的控制。HUR是一种调节RNA水平的RNA结合蛋白 转录及其在细胞内的翻译。尽管HUR因其在 除了增殖、炎症和凋亡外，它作为代谢感受器的作用还相对未知。我们的 初步数据显示，骨骼肌特异性HUR基因敲除小鼠表现出更强的胰岛素抵抗 以及相对于对照动物的肥胖度。有趣的是，这些小鼠表现出HUR靶标水平的增加 同时也显示这些转录本的翻译蛋白水平降低。新陈代谢不良的人 骨骼肌中HUR下调导致的预后也与我们收集的数据相补充 用于新陈代谢不健康的男性和女性人体骨骼肌样本。拟议的目标将 因此，验证HUR靶向核糖体转录物促进新陈代谢的假设 通过影响mTOR信号通路的灵活性。 非常重要的是，沃费尔博士将学习新的方法学技术，以发展他的职业生涯 一位专注于RNA生物学和新陈代谢的独立研究员。本提案中的方法包括 转基因小鼠模型的产生和表型、代谢室和放射性代谢物的使用 化验、生物信息学和分子生物学。这些技术方面的培训也将提供初步的 开发未来项目所需的数据，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 还有肥胖症。这是沃费尔博士长期的研究期望，他已经组建了一支出色的团队 在与此计划相关的领域拥有丰富经验的导师和合作者，他们将提供 指导，以确保沃菲尔博士实现独立。

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.