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（由申请人提供）：与蛋白质、碳水化合物和脂质的异常加工相关的代谢疾病是显着发病和死亡的原因。核受体、肝脏 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，与类视黄醇 X 受体 (RXR) 作为异二聚体发挥作用。 LXRa 和 LXRß 在胆固醇生理学和脂质代谢中发挥重要作用，并且与多种疾病的病理学有关，包括动脉粥样硬化、癌症和肥胖。对 LXRa 缺陷小鼠的详细检查揭示了有关其在调节代谢途径（包括脂质代谢）中的作用的大量信息。 LXR 在代谢中的潜在药理学作用已通过合成激动剂确定，但本研究的重点是使用反向激动剂治疗脂肪肝疾病。我们已经确定了一个 新型合成 LXR 反向激动剂，具有特异性抑制肝脏中 LXR 靶基因表达的能力，因此具有抑制脂肪性肝炎的潜力。长期目标是使用这些化合物作为工具来研究合成 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具体目标中得到检验： 具体目标 1 将检查 SR9238 影响 LXR 介导的脂肪生成、炎症和胆固醇调节的机制；具体目标 2 将评估 SR9238 在小鼠模型中治疗非酒精性脂肪性肝炎 (NASH) 的潜力。配体调节的核激素受体已被明确证明是药物开发的有效靶标。我们预测这些研究将为 LXR 治疗脂肪性肝病和其他潜在代谢性疾病的新疗法提供基础。