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

使用 LRH-1 小分子激动剂调节代谢基因表达

• 批准号: 9911759
• 负责人: Elizabeth Joy Millings
• 金额: $ 5.43万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2021-01-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9911759
• 关键词: Address; Adult; Affect; Agonist; Binding; Biochemistry; Blood Glucose; Body Weight; Cell Line; Cells; Characteristics; Control Groups; Country; Data; Development; Diet; Disease; Disease model; Dose; Education; Educational process of instructing; Effectiveness; Endocrine; Ensure; Environment; Exhibits; Fatty Liver; Fatty acid glycerol esters; Fellowship; Gene Activation; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Genetic Transcription; Goals; Hepatic; Hepatocyte; High Fat Diet; Homeostasis; Homologous Gene; Human; In Vitro; Insulin Resistance; Knockout Mice; Lecithin; Ligand Binding; Ligands; Lipids; Liver; Liver diseases; Measures; Mediating; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolic dysfunction; Metabolic syndrome; Methods; Mus; NR5A2 gene; Nature; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Orphan Receptor; Nuclear Receptors; Obese Mice; Obesity; Operative Surgical Procedures; Pathway Analysis; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Phospholipids; Physiology; Play; Population; Receptor Activation; Receptor Gene; Regulation; Research; Research Personnel; Science; Series; Serum; Signal Pathway; Signal Transduction; Solubility; Specificity; Structure; Symptoms; Testing; Therapeutic; Training; Transgenic Mice; Universities; base; blood glucose regulation; chromatin immunoprecipitation; design; effectiveness testing; glucose metabolism; glucose tolerance; improved; in vivo; in vivo Model; insulin sensitivity; liver function; medical schools; mouse model; non-alcoholic fatty liver disease; novel; programs; promoter; receptor; small molecule; therapeutic target; transcriptome sequencing; transcriptomics

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.

项目总结/摘要 肝同源受体（LRH-1）是一种核受体，在肝脏代谢信号传导中起关键作用。 在肥胖背景下靶向LRH-1导致胰岛素敏感性和肝脏脂质的显著改善 体内平衡这表明LRH-1可能是代谢性疾病的重要治疗靶标， 2型糖尿病与脂肪肝 使用基于结构的设计，已经开发了新型LRH-1调节剂，其有效地激活LRH-1， 在体外和体内。然而，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，RNA-seq和ChIP-seq方法将用于 研究具有不同结合机制的合成激动剂如何交替调节LRH-1靶标 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 激动剂来治疗他们的代谢功能障碍。将测量脂质和葡萄糖稳态参数， 阐明LRH-1激动剂逆转代谢症状的有效性。确保激动剂特异性 对于LRH-1，LRH-1 KO小鼠将用作实验对照。作为首批针对LRH-1的研究之一， 与合成激动剂，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和外科学系进行 医学院，将包括转录组测序，脂质组学和小鼠实验室的实践培训。 转基因和生理学。培训将在埃默里大学令人兴奋的智力环境中进行 大学和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 额外的教学和专业发展机会。总而言之， 这里所描述的结合特殊的培训环境将确保成功 将申请人培养成独立的研究者。