Regulation and Function of Thioredoxin Interacting Protein (Txnip) in Nonalcoholic Steatohepatitis (NASH)

硫氧还蛋白相互作用蛋白 (Txnip) 在非酒精性脂肪性肝炎 (NASH) 中的调节和功能

• 批准号: 10736673
• 负责人: Ling Yang
• 金额: $ 34.33万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10736673
• 关键词: Adenoviruses; Affect; Antisense RNA; Apoptosis; Apoptotic; Binding; Binding Proteins; Biological Assay; CCAAT-Enhancer-Binding Proteins; Cell model; Cirrhosis; Clinical Treatment; Clinical Trials; Data; Dependovirus; Development; Diabetes Mellitus; Down-Regulation; Epidemic; FDA approved; Gene Proteins; Genes; Genetic; Genetic Transcription; Hepatic; Hepatocyte; Homologous Protein; Human; Impairment; Knockout Mice; Kupffer Cells; Life; Liver; Malignant neoplasm of liver; Mediating; Metabolic; Metabolic Diseases; Modeling; Molecular; Mus; Organ; Pathogenesis; Pathogenicity; Patients; Pilot Projects; Play; Protein Inhibition; Proteins; Public Health; RNA; Regulation; Reporting; Role; Serotyping; Stress; TXNIP gene; Testing; Therapeutic; Tissues; Translations; Ubiquitination; Untranslated RNA; adenoviral mediated; cell type; chronic liver disease; clinical application; cost; gene function; genetic manipulation; genomic locus; improved; inhibitor; innovation; insight; knock-down; mouse model; new therapeutic target; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; novel therapeutic intervention; overexpression; polysome profiling; protein degradation; protein expression; protein function; protein protein interaction; small hairpin RNA; targeted treatment; therapeutically effective; transcription factor; ubiquitin-protein ligase

PROJECT SUMMARY The worldwide epidemic of nonalcoholic fatty liver disease (NAFLD) has become a severe and costly threat to public health. The current therapeutic options for NAFLD are exceedingly limited, especially for its severe form - nonalcoholic steatohepatitis (NASH), which has no FDA-approved therapy. There is an urgent need to identify novel therapeutic targets for NASH treatment. Thioredoxin interacting protein (Txnip) is a stress-induced gene, and it has been implicated in NASH. However, the role of Txnip in NASH is controversial, which may be attributed to the following two issues. Firstly, there are two genes in the Txnip gene locus: Txnip and Txnip antisense long non-coding RNA Gm15441. Genetic deletion of Txnip also deletes part of Gm15441. Secondly, Txnip plays critical roles in other metabolic organs, which interferes with its function in the liver. Therefore, previous studies using Txnip global knockout mice were not able to reveal the liver-specific role of Txnip in NASH. Our preliminary data demonstrate that Txnip protein is abnormally accumulated in NASH mouse livers. Our preliminary studies also suggest that Txnip may promote hepatocyte apoptosis. Given that excessive hepatocyte apoptosis drives NASH development, therefore, we propose a central hypothesis that inhibition of hepatic Txnip alleviates NASH. In Aim 1, an antisense RNA based Txnip translational inhibitor will be developed for NASH treatment. In Aim 2, we will dissect the functional role and mechanism of Txnip in NASH mouse liver. In Aim 3, we will investigate a novel mechanism that causes Txnip protein accumulation in NASH mouse liver. Completion of this proposal will provide critical insights into the functions and mechanisms of Txnip in NASH development. These studies will also lead to the development of novel therapeutic strategies for NASH treatment.

项目摘要 非酒精性脂肪性肝病（NAFLD）的全球流行已成为严重且昂贵的威胁， 公共卫生目前NAFLD的治疗选择非常有限，特别是对于其严重形式- 非酒精性脂肪性肝炎（NASH），没有FDA批准的治疗。迫切需要查明 NASH治疗的新治疗靶点。硫氧还蛋白相互作用蛋白（Txnip）是一个应激诱导基因， 它与NASH有关然而，Txnip在NASH中的作用是有争议的，这可能归因于 以下两个问题。首先，在Txnip基因座中存在两个基因：Txnip和Txnip反义长链 非编码RNA Gm 15441。Txnip的遗传缺失也缺失了Gm 15441的一部分。其次，Txnip播放 在其他代谢器官中起关键作用，这会干扰其在肝脏中的功能。因此，以往的研究 使用Txnip整体敲除小鼠不能揭示Txnip在NASH中的肝脏特异性作用。我们的初步 数据表明Txnip蛋白在NASH小鼠肝脏中异常积累。我们的初步研究 提示Txnip可促进肝细胞凋亡。鉴于过度的肝细胞凋亡 因此，针对NASH的发展，我们提出了一个中心假设，即抑制肝Txnip会加重NASH。 在目标1中，将开发基于反义RNA的Txnip翻译抑制剂用于NASH治疗。在目标2中， 我们将对Txnip在NASH小鼠肝脏中的功能作用和机制进行深入研究。在目标3中，我们将研究 导致Txnip蛋白在NASH小鼠肝脏中积累的新机制。完成本提案将 为Txnip在NASH发展中的功能和机制提供重要见解。这些研究将 还导致NASH治疗的新治疗策略的开发。