Activated ER alpha as compensation for HuR controlled lipid oxidation in skeletal muscle

激活 ER α 作为 HuR 控制骨骼肌脂质氧化的补偿

• 批准号: 10742019
• 负责人: Jaycob Dalton Warfel
• 金额: $ 20.59万
• 依托单位: CHRISTIAN BROTHERS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-11 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10742019
• 关键词: Address; Animals; Binding; Biological; Bypass; Carbohydrates; Cell Culture Techniques; Cells; Compensation; Data; Defect; Development; Diabetes Mellitus; Disease; Estradiol; Estrogen Receptor alpha; Estrogens; Excision; Fatty Acids; Fatty acid glycerol esters; Female; Foundations; Genetic Transcription; Goals; HuR protein; Human; Impairment; In Vitro; Insulin Resistance; Knowledge; Lipids; Mentored Research Scientist Development Award; Messenger RNA; Metabolic; Metabolic Control; Metabolic Diseases; Molecular; Mus; Muscle; Muscle Cells; Obesity; Onset of illness; Organism; Peroxisome Proliferator-Activated Receptors; Phenotype; Physiological; Play; Publishing; RNA Binding; RNA immunoprecipitation sequencing; RNA-Binding Proteins; Reporting; Research; Role; Skeletal Muscle; Source; Supplementation; Testing; Training; United States National Institutes of Health; adverse outcome; comparison control; design; experience; experimental study; fatty acid oxidation; flexibility; in vivo; insight; knockout animal; male; mouse model; novel; oxidation; oxidized lipid; preservation; prevent; sex; sexual dimorphism; transcription factor; transcriptome; treatment strategy

PROJECT SUMMARY/ABSTRACT Metabolic flexibility is the capacity for an organism to adapt fuel oxidation to fuel availability. We have shown that mice lacking the RNA binding protein HuR in skeletal muscle are less metabolically flexible than controls, with a decreased ability to oxidize lipids in skeletal muscle. Our recently published findings show that this phenotype is specific to male animals, and that female animals lacking HuR in skeletal muscle do not have decreased lipid oxidation relative to controls. The mechanistic underpinnings of this sexual dimorphism are unknown. This proposal tests the overarching hypothesis that activated ERα can promote lipid oxidation through the PPAR transcription factors, allowing females to bypass HuR-controlled lipid oxidation due to higher levels of circulating estrogen. Two specific aims are proposed: 1) Investigate HuR and ERα regulated skeletal muscle fatty acid oxidation; and 2) Test the ability of 17β-estradiol to stimulate fatty acid oxidation in HuR-deficient muscle. The completion of these aims will provide insights into sex-specific control of skeletal muscle lipid oxidation, which may facilitate development of sex-specific strategies for treatment of metabolic disease. Importantly, these studies will build upon data and experience obtained from my K01 award while also providing a novel extension of my previous training and current knowledge regarding HuR control of metabolic flexibility. The data generated from this proposal will provide a foundation for R01 proposals designed to investigate the molecular mechanisms controlling metabolic flexibility in mice and humans, which is consistent with my long- term research goals.

项目摘要/摘要 新陈代谢灵活性是生物体适应燃料氧化以适应燃料可用性的能力。我们已经展示了 在骨骼肌中缺乏RNA结合蛋白HUR的小鼠的新陈代谢灵活性低于对照组， 骨骼肌中氧化脂质的能力下降。我们最近发表的研究结果表明，这一点 表型是雄性动物特有的，而骨骼肌中缺乏HUR的雌性动物没有 与对照组相比，减少了脂质氧化。这种性别二型性的机械基础是 未知。这一建议验证了最重要的假设，即激活ERα可以通过以下方式促进脂质氧化 PPAR转录因子，允许雌性绕过Hur控制的脂质氧化，这是由于较高水平的 循环中的雌激素。提出两个具体目标：1)研究HUR和ERα对骨骼肌的调控 2)检测17β-雌二醇刺激HUR缺乏症患者脂肪酸氧化的能力 肌肉。这些目标的完成将提供对骨骼肌脂类的性别特异性控制的见解 氧化，这可能有助于制定针对性别的代谢性疾病治疗策略。 重要的是，这些研究将建立在从我的K01奖中获得的数据和经验的基础上，同时也提供 这是我之前训练和目前关于HUR控制代谢灵活性的新知识的一个新的扩展。 本提案产生的数据将为R01提案提供基础，旨在调查 控制小鼠和人类代谢灵活性的分子机制，这与我长期以来的 学期研究目标。