Modulating Metabolic Gene Expression with Small Molecule Agonists for LRH-1

项目摘要/摘要 肝脏同源受体(LRH-1)是一种在肝脏代谢信号中起关键作用的核受体。 在肥胖的背景下靶向LRH-1可显著改善胰岛素敏感性和肝脂 动态平衡。这表明LRH-1可能是代谢性疾病的重要治疗靶点，如 2型糖尿病和脂肪肝。 利用基于结构的设计，已经开发出能够有效激活LRH-1和LRH-1的新型LRH-1调制器 在体外和体内。然而，目前尚不清楚用合成激动剂激活LRH-1将如何调节 基因表达和代谢信号通路。在目标1中，将使用RNA-SEQ和CHIP-SEQ方法来 研究具有不同结合机制的合成激动剂如何交替调节LRH-1靶点 原代人肝细胞中的基因。在目标2中，饮食诱导的肥胖小鼠将被给予合成的LRH-1 用激动剂来治疗他们的代谢功能障碍。血脂和血糖稳态的参数将被测量到 阐明LRH-1激动剂逆转代谢症状的有效性。确保激动剂的特异性 对于LRH-1，将以LRH-1 KO小鼠作为实验对照。作为首批针对LRH-1的研究之一 体内合成激动剂，这项研究将提供有关治疗潜力的重要信息 靶向LRH-1治疗代谢性疾病。 奖学金培训将在埃默里大学的生物化学系和外科系进行 并将包括转录组测序、脂质组学和小鼠的实践培训 转基因和生理学。培训将在埃默里大学激动人心的智力环境中进行 并利用几个合作者和研究核心的专业知识。IRACDA奖学金 在研究和科学教学(第一)计划和博士后教育办公室也将提供 提供更多的教学和专业发展机会。总而言之，开创性的研究 此处介绍的内容与卓越的培训环境相结合，将确保成功 将这位申请者发展成为独立的研究调查员。

Project Summary/Abstract Liver homolog receptor (LRH-1) is a nuclear receptor that plays a key role in hepatic metabolic signaling. Targeting LRH-1 in the context of obesity results in marked improvements in insulin sensitivity and hepatic lipid homeostasis. This suggests that LRH-1 could be an important therapeutic target in metabolic diseases such as Type 2 diabetes and fatty liver disease. Using structure-based design, novel LRH-1 modulators have been developed that potently activate LRH-1 both in vitro and in vivo. However, it remains unknown how activating LRH-1 with synthetic agonists will modulate gene expression and metabolic signaling pathways. In Aim 1, RNA-seq and ChIP-seq methods will be used to examine how synthetic agonists with different binding mechanisms can alternately regulate LRH-1 target genes in primary human hepatocytes. In Aim 2, diet-induced obese mice will be dosed with a synthetic LRH-1 agonist to treat their metabolic dysfunction. Parameters of lipid and glucose homeostasis will be measured to elucidate the effectiveness of an LRH-1 agonist in reversing metabolic symptoms. To ensure agonist specificity for LRH-1, LRH-1 KO mice will be used as experimental controls. As one of the first studies to target LRH-1 in vivo with synthetic agonists, this research will provide vital information about the therapeutic potential of targeting LRH-1 to treat metabolic diseases. Fellowship training will be conducted in the departments of Biochemistry and Surgery at Emory University School of Medicine and will include hands-on training in transcriptomic sequencing, lipidomics, and mouse transgenics and physiology. Training will take place in the stimulating intellectual environment at Emory University and draw upon the expertise of several collaborators and research cores. The IRACDA Fellowships in Research and Science Teaching (FIRST) program and the Office of Postdoctoral Education will also provide additional teaching and professional development opportunities. In summary, the pioneering research described here in combination with the exceptional training environment will ensure the successful development of this applicant into an independent research investigator.