Dissecting the Intracellular and Extracellular Role of TREM2 in the Pathogenesis of Non-Alcoholic Steatohepatitis.

剖析 TREM2 在非酒精性脂肪性肝炎发病机制中的细胞内和细胞外作用。

• 批准号: 10720352
• 负责人: Debanjan Dhar
• 金额: $ 56万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10720352
• 关键词: 3-Dimensional; Acceleration; Address; Affect; Animal Model; Antibodies; Area; Benign; Binding; Bone Marrow; Cell surface; Cells; Cicatrix; Cleaved cell; Data; Development; Diet; Disease Progression; Early Diagnosis; Extracellular Domain; Fatty Liver; Fibrosis; Foundations; Functional disorder; Future; Gene Delivery; Goals; Health Care Costs; Hepatocyte; Human; In Vitro; Inflammatory; Knock-out; Life Style Modification; Ligand Binding; Ligands; Lipids; Liver; Liver diseases; Macrophage; Macrophage Activation; Malignant neoplasm of liver; Measures; Mediating; Membrane; Metabolic syndrome; Mission; Modeling; Molecular; Mus; Mutation; Myeloid Cells; Pathogenesis; Pathway interactions; Patients; Physiological; Plasma; Play; Population; Prevention; Primary carcinoma of the liver cells; Property; Resolution; Role; Sampling; Serum; Signal Pathway; Signal Transduction; Site; TREM2 gene; TYROBP gene; Therapeutic; Therapeutic Agents; Therapeutic Effect; United States National Institutes of Health; cancer transplantation; cell injury; chronic liver inflammation; clinical translation; cytokine; epigenetic regulation; epigenomics; extracellular; fatty liver disease; genetic signature; in vivo Model; insight; liver injury; liver transplantation; mouse model; new therapeutic target; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; novel therapeutic intervention; novel therapeutics; overexpression; prevent; receptor; response; transcription factor; transmission process

Abstract: Non-alcoholic steatohepatitis (NASH) is the fastest growing cause of liver cancer and liver transplant in the U.S. There is currently no approved treatment for NASH and the mechanistic understanding of why some patients with fatty liver maintain a benign condition while others progress to NASH is not clear. Macrophages play a pivotal role in NASH pathogenesis. Accumulating evidence suggest that ‘triggering receptor expressed on myeloid cells’ (TREM2) is overexpressed in NASH associated macrophages. Interestingly, even though TREM2 expression is increased during NASH, its absence exacerbates NASH and fibrosis development. This indicates that TREM2 is protective in NASH and fibrosis progression. However, the mechanism of TREM2 signaling remains poorly understood. Moreover, upon ligand engagement, TREM2 gets cleaved from the cell surface into a soluble form (sTREM2) that can be detected in the serum. We found that sTREM2 levels increase with NAFLD and NASH progression, however, the trans-signaling axis of sTREM2 is an area that has not been addressed in the field yet. sTREM2 has the ability to soak up inflammatory ligands such as LPS and lipids as well as bind to macrophages. However, whether sTREM2 can bind and influence downstream signaling in other cells remain unknown. We discovered that sTREM2 itself has NASH protective as well as therapeutic abilities. Introduction of sTREM2 fragment into mice that already had advanced NASH had profound effects on NASH and fibrosis resolution. The goal of this proposal is to better understand how TREM2 exerts its protective functions and dissect the intracellular and trans-signaling axes of TREM2. We will use mouse models of NASH and HCC that closely mimics diet induced metabolic syndrome and human NASH gene signature as well as primary cultures of both mouse and human liver cells in order to assess the following 2 Specific Aims: Aim 1 will identify the key intracellular TREM2 signaling pathways that exerts its protective actions in controlling NASH development. We will also identify the transcription factors responsible for TREM2 expression in NASH associated macrophages. Aim 2 will elucidate the trans-signaling properties of sTREM2 and whether sTREM2 is directly involved in disease progression. The proposed studies will provide key insights into the mechanisms of NASH and HCC development. The findings from this study will lay the foundation for future development and refinement of sTREM2 as a novel therapeutic agent for NASH-Fibrosis and HCC.

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