Selective mTORC1 inhibition to prevent and treat NAFLD and NASH

选择性 mTORC1 抑制预防和治疗 NAFLD 和 NASH

基本信息

批准号：
10470224
负责人：
Zoltan P Arany
金额：
$ 48.48万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-15 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10470224
关键词：
ADD-1 protein Biogenesis Characteristics Cirrhosis Complex Data Diet Disease EIF4EBP1 gene Epidemic FDA approved FRAP1 gene Feedback GTP-Binding Proteins GTPase-Activating Proteins Grant Hepatic Hepatocyte Homeostasis Human In Vitro Knock-out Knockout Mice Lead Lipids Literature Liver Liver Fibrosis Malignant Neoplasms Mediating Metabolic Mitochondria Molecular Mus Mutagenesis Pathway interactions Persons Phosphorylation Physiological Prevention Primary carcinoma of the liver cells Process Protein Inhibition Reporting Role Signal Transduction Small Interfering RNA Steatohepatitis TFE3 gene TSC1 gene Technology Testing Therapeutic Tumor Suppressor Proteins arm base cell type detection of nutrient experimental study fatty acid oxidation in vivo lipid biosynthesis liver cancer model liver injury new therapeutic target non-alcoholic fatty liver disease nonalcoholic steatohepatitis novel phosphoproteomics prevent response side effect small hairpin RNA stem therapeutic siRNA therapeutic target transcription factor translational potential

项目摘要

As many as 100 million people in the US have non-alcoholic fatty liver disease (NAFLD), which can lead to hepatic injury and fibrosis, characteristics of non-alcoholic steatohepatitis (NASH), and in turn can progress to cirrhosis and hepatocellular carcinoma cancer (HCC). To date there are no FDA-approved therapy for NAFLD or NASH. The mTOR pathway is a critical nutrient sensing pathway in many cell types, including hepatocytes. mTORC1 has thus been studied as a target to modulate lipid homeostasis in the liver, but its role remains unclear, with multiple excellent studies lead to seemingly opposing conclusions. We have now uncovered a highly specific branch of mTORC1 signaling in the liver, regulated by the FLCN protein, the inhibition of which leads to coordinated activation of lipid catabolic pathways and strong suppression of de novo lipogenesis (DNL), thereby potently protecting from both NAFLD and ensuing NASH. We thus hypothesize that FLCN represents a uniquely attractive therapeutic target to treat these diseases. We propose experiments to: 1. Understand how, mechanistically, the FLCN arm of mTORC1 signaling suppresses DNL 2. Understand how, mechanistically, the FLCN and canonical arms of mTORC1 signaling feedback on each other 3. Formally test the validity of FLCN as a therapeutic target to treat the NAFLD/NASH/HCC spectrum.

美国有多达 1 亿人患有非酒精性脂肪性肝病 (NAFLD)，这种疾病可导致肝损伤和纤维化，这是非酒精性脂肪性肝炎 (NASH) 的特征，进而可发展为肝硬化和肝细胞癌（肝癌）。迄今为止，尚无 FDA 批准的 NAFLD 或 NASH 治疗方法。 mTOR 通路是许多细胞类型（包括肝细胞）中的关键营养传感通路。因此，mTORC1 作为调节肝脏脂质稳态的靶点进行了研究，但其作用仍不清楚，多项优秀研究得出了看似相反的结论。我们现在发现了肝脏中 mTORC1 信号传导的一个高度特异性的分支，该分支受 FLCN 蛋白的调节，其抑制导致脂质分解代谢途径的协调激活和从头脂肪生成 (DNL) 的强烈抑制，从而有效预防 NAFLD以及随之而来的 NASH。因此，我们假设 FLCN 代表了治疗这些疾病的独特有吸引力的治疗靶点。我们提出实验目的是： 1. 从机制上了解 mTORC1 信号传导的 FLCN 臂如何抑制 DNL 2. 从机制上了解 mTORC1 信号传导的 FLCN 臂和规范臂如何相互反馈 3. 正式测试 FLCN 作为治疗药物的有效性目标是治疗 NAFLD/NASH/HCC 谱系。