Investigating Synthetic Ligands for the Treatment of NASH

研究治疗 NASH 的合成配体

• 批准号: 8909821
• 负责人: Kristine Griffett
• 金额: $ 5.6万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-05 至 2018-01-04
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8909821
• 关键词: Adverse effects; Agonist; Atherosclerosis; Carbohydrates; Cholesterol; Development; Diabetes Mellitus; Diet; Disease; Drug Targeting; Fatty Liver; Gene Expression; Genes; Genetic Models; Hepatic; Inflammation; Life; Ligands; Lipids; Liver; Liver diseases; Malignant Neoplasms; Mediating; Metabolic Diseases; Metabolic Pathway; Metabolism; Morbidity - disease rate; Mus; Nuclear Hormone Receptors; Nuclear Receptors; Obese Mice; Obesity; Orphan; Pathology; Pathway interactions; Pharmacologic Substance; Physiology; Play; Process; Proteins; RXR; Regulation; Role; Steatohepatitis; Testing; Therapeutic; Work; base; fatty acid oxidation; lipid biosynthesis; lipid metabolism; liver metabolism; member; mortality; mouse model; new therapeutic target; nonalcoholic steatohepatitis; novel; public health relevance; receptor; sensor; tool

 DESCRIPTION (provided by applicant): Metabolic diseases, associated with abnormal processing of proteins, carbohydrates, and lipids, are the cause of significant morbidity and mortality. The nuclear receptors, liver X receptor a, and -ß (LXRa and LXRß), were originally identified as orphan members of the nuclear receptor (NR) superfamily that function as heterodimers with the retinoid X receptor (RXR). Both LXRa and LXRß play important roles in cholesterol physiology and lipid metabolism, and have been implicated in the pathology of several diseases, including athereosclerosis, cancer, and obesity. Detailed examination of mice deficient in LXRa have revealed a significant amount of information regarding its role in regulating metabolic pathways, including lipid metabolism. Potential pharmacological roles of LXR in metabolism have been identified using synthetic agonists, however our focus for this study is the use of inverse agonists in the treatment of fatty liver diseases. We have identified a novel synthetic LXR inverse agonist that displays the ability to specifically suppress LXR target gene expression specifically in the liver, thus having the potential to suppress steatohepatitis. The long-term objective is to use these compounds as tools to study the effects of synthetic LXR ligands on diseases of the liver. We hypothesize that LXR inverse agonists can suppress the effects Fatty Liver Diseases in mouse models. Our hypothesis will be tested in the following specific aims: Specific Aim 1 will examine the mechanism(s) by which SR9238 effects LXR-mediated lipogenesis, inflammation, and cholesterol regulation; Specific Aim 2 will evaluate the potential for SR9238 as a therapeutic in Non- Alcoholic Steatohepatitis (NASH) in mouse models of the disease. Ligand-regulated nuclear hormone receptors have been definitively shown to be effective targets for the development of pharmaceuticals. We predict that these studies will provide the basis for novel therapeutics targeting LXR for the treatment of fatty live diseases and potentially other metabolic disorders.

 描述（由适用提供）：代谢疾病，与蛋白质，碳水化合物和脂质的异常加工有关，是发病率明显的原因。核受体肝X受体A和-ß（LXRA和LXRß）最初被鉴定为核受体（NR）超家族的孤儿成员，该成员是具有类维生素X受体（RXR）的异二聚体。 LXRA和LXRß都在胆固醇生理和脂质代谢中起重要作用，并且在包括动脉粥样硬化，癌症和持有在内的多种疾病的病理学中隐含了重要作用。对LXRA缺乏的小鼠的详细检查显示，有关其在控制代谢途径（包括脂质代谢）中的作用的大量信息。 LXR在代谢中的潜在药物作用已被使用合成激动剂，但是我们的研究重点是使用反激动剂在治疗脂肪肝疾病中。我们已经确定了 新型的合成LXR反向激动剂显示出特异性抑制LXR靶基因表达的能力，因此具有抑制脂肪性肝炎的潜力。长期目标是将这些化合物用作研究合成LXR配体对肝脏疾病的影响。我们假设LXR反向激动剂可以抑制小鼠模型中脂肪肝疾病的影响。我们的假设将在以下测试中进行检验。具体目的：具体目标1将检查SR9238影响LXR介导的脂肪生成，感染和胆固醇调节的机制；具体目标2将评估SR9238作为该疾病小鼠模型中非酒精性脂肪性肝炎（NASH）治疗的潜力。由配体调节的核马酮受体已被明确证明是用于开发药物的有效靶标。我们预测，这些研究将为靶向LXR的新型治疗提供基础，以治疗脂肪活疾病和潜在的其他代谢疾病。