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.

项目概要 非酒精性脂肪肝病 (NAFLD) 在全球范围内的流行已成为对人类造成严重且代价高昂的威胁 公共卫生。目前 NAFLD 的治疗选择极其有限，特别是对于其严重形式 - 非酒精性脂肪性肝炎 (NASH)，尚无 FDA 批准的治疗方法。迫切需要识别 NASH 治疗的新治疗靶点。硫氧还蛋白相互作用蛋白（Txnip）是一种应激诱导基因， 它与NASH有关。然而，Txnip 在 NASH 中的作用存在争议，这可能归因于 到以下两个问题。首先，Txnip基因座中有两个基因：Txnip和Txnip反义长 非编码RNA Gm15441。 Txnip 的基因删除也会删除 Gm15441 的一部分。其次，Txnip 扮演 在其他代谢器官中发挥关键作用，从而干扰其在肝脏中的功能。因此，以往的研究 使用 Txnip 全局基因敲除小鼠无法揭示 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 还提示Txnip可能促进肝细胞凋亡。鉴于过度的肝细胞凋亡驱动 因此，我们提出了一个中心假设：抑制肝脏 Txnip 可以缓解 NASH。 在目标 1 中，将开发一种基于反义 RNA 的 Txnip 翻译抑制剂用于 NASH 治疗。在目标 2 中， 我们将剖析Txnip在NASH小鼠肝脏中的功能作用和机制。在目标 3 中，我们将调查 导致 NASH 小鼠肝脏中 Txnip 蛋白积累的新机制。该提案的完成将 提供有关 Txnip 在 NASH 发展中的功能和机制的重要见解。这些研究将 也导致 NASH 治疗新治疗策略的开发。