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.

抽象的： 非酒精性脂肪性肝炎 (NASH) 是美国肝癌和肝移植增长最快的原因。 目前尚无批准的 NASH 治疗方法，也没有对某些患者出现这种症状的机制的理解 脂肪肝患者保持良性状态，而其他人进展为 NASH 尚不清楚。巨噬细胞发挥着 NASH 发病机制中发挥关键作用。越来越多的证据表明“触发受体表达于 骨髓细胞 (TREM2) 在 NASH 相关巨噬细胞中过度表达。有趣的是，尽管 TREM2 NASH 期间表达增加，其缺失会加剧 NASH 和纤维化的发展。这表明 TREM2 对 NASH 和纤维化进展具有保护作用。然而，TREM2 信号传导机制 仍然知之甚少。 此外，配体结合后，TREM2 从细胞表面裂解成可溶形式 (sTREM2) 可以在血清中检测到。我们发现 sTREM2 水平随着 NAFLD 和 NASH 的进展而增加， 然而，sTREM2 的跨信号轴是该领域尚未解决的一个领域。 STREM2 具有吸收脂多糖和脂质等炎症配体以及与巨噬细胞结合的能力。然而， sTREM2 是否可以结合并影响其他细胞中的下游信号传导仍不清楚。我们发现 sTREM2 本身具有 NASH 保护和治疗能力。将sTREM2片段引入 已经患有晚期 NASH 的小鼠对 NASH 和纤维化的消退具有深远的影响。 该提案的目的是更好地了解 TREM2 如何发挥其保护功能并剖析 TREM2 的细胞内和跨信号轴。 我们将使用 NASH 和 HCC 小鼠模型，该模型非常模仿饮食引起的代谢综合征和人类 NASH 基因特征以及小鼠和人类肝细胞的原代培养物，以评估 以下 2 个具体目标：目标 1 将确定发挥其作用的关键细胞内 TREM2 信号通路 控制 NASH 发展的保护措施。我们还将确定负责的转录因子 TREM2 在 NASH 相关巨噬细胞中的表达。目标 2 将阐明转信号特性 sTREM2 以及 sTREM2 是否直接参与疾病进展。拟议的研究将提供 NASH 和 HCC 发展机制的关键见解。这项研究的结果将奠定 为 sTREM2 作为 NASH 纤维化新型治疗剂的未来开发和完善奠定了基础 和肝癌。