Innate Immunity in NASH

NASH 中的先天免疫

基本信息

批准号：
10720481
负责人：
Juli Bai
金额：
$ 47.4万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10720481
关键词：
Adipocytes Apoptosis Apoptotic Binding Biology Cell Death Cell membrane Cells Cessation of life Chronic Cyclic GMP DNA DNA Binding Development Diet Disease Ectopic Expression Equilibrium Event Fibrosis Goals Guanosine Triphosphate Hepatocyte Homeostasis Immune Immune signaling Impairment In Vitro Inflammation Innate Immune System Insulin Resistance Knock-out Kupffer Cells Link Liver Liver Fibrosis Liver diseases Macrophage Mediating Membrane Metabolic Diseases Molecular Mus Natural Immunity Nature Organ Outcome Pathogenesis Pathologic Pathway interactions Phagocytes Phagocytosis Phagocytosis Induction Phagosomes Pharmaceutical Preparations Phase Phosphatidylinositol 4,5-Diphosphate Phosphatidylinositols Physiological Play Population Primary carcinoma of the liver cells Regulation Rest Role SYK gene Signal Transduction Stimulator of Interferon Genes Testing Therapeutic Thinking Tissues cell injury chemokine cytokine diet-induced obesity ds-DNA end stage liver disease enzyme activity epidemiology study immune activation immunoregulation improved in vivo injured innate immune pathways innate immune sensing liver inflammation monocyte new therapeutic target non-alcoholic fatty liver disease nonalcoholic steatohepatitis novel novel therapeutics prevent protective pathway recruit sensor spatiotemporal therapeutically effective tissue injury

项目摘要

Nonalcoholic steatohepatitis (NASH), a cell death and inflammation-associated nonalcoholic fatty liver disease (NAFLD), is the leading cause of hepatocellular carcinoma (HCC) and end-stage liver failure worldwide. There is no effective therapeutic drug for NASH to date, highlighting an urgent need for the identification of novel targets for this devastating disease. Evidence cumulated over the past decade strongly suggest that the innate immune system, specifically the liver-resident macrophages (Kupffer cells) and recruited monocyte-derived macrophages, play a key role in NASH progression and pathogenesis. The current study aims to elucidate the mechanisms by which macrophage cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway regulates liver fibrosis and NASH pathogenesis. We found that macrophage-specific knockout of cGAS or STING promotes liver inflammation, apoptosis, and fibrosis, suggesting this DNA sensing innate immune pathway protects, rather than promotes, NASH progression in mice. However, how cGAS or STING deficiency leads to NASH pathogenesis remains unknown. Our preliminary study suggests that macrophage cGAS may suppress NASH development by facilitating macrophage phagocytosis via both STING-dependent and independent novel mechanisms. To test this hypothesis, we will 1) delineate the STING-independent molecular mechanism by which cGAS promotes macrophages phagocytosis; 2) Elucidate the STING-dependent signaling mechanism by which cGAS regulates macrophage phagocytosis; and 3) Explore the physiological role of cGAS-regulated phagocytosis in preventing liver fibrosis and NASH. Our study will dissect a novel role mechanism by which cGAS regulates macrophage phagocytosis and prevents NASH. The comprehensive understanding of the fundamental functions of the innate immunity and macrophage biology will not only provide a proof-of-concept for rethinking the nature of this devastating liver disease, but also open a new therapeutic avenue for developing therapeutic treatment of NASH.

非酒精性脂肪性肝炎（NASH），细胞死亡和与炎症相关的非酒精性脂肪肝病（NAFLD）是全球肝细胞癌（HCC）和终末期肝衰竭的主要原因。有迄今为止，没有有效的NASH治疗药物，强调迫切需要确定新目标对于这种毁灭性疾病。过去十年中，证据累积了，强烈表明先天免疫系统，特别是肝居民巨噬细胞（库普弗细胞），并招募了单核细胞巨噬细胞，在纳什进展和发病机理中起关键作用。当前的研究旨在阐明巨噬细胞循环GMP-AMP合酶（CGAS）的机制 - 干扰素基因的刺激剂（sting）途径调节肝纤维化和NASH发病机理。我们发现CGA的巨噬细胞特异性敲除或刺痛会促进肝脏炎症，凋亡和纤维化，这表明这种DNA感应先天免疫途径可以保护小鼠的纳什进展而不是促进nash的进展。但是，CGA或刺痛的缺陷如何导致NASH发病机理仍然未知。我们的初步研究表明，巨噬细胞CGA可能通过通过sting依赖性和独立的新型机制。为了检验这一假设，我们将1）描绘与刺激的分子 CGA促进巨噬细胞吞噬作用的机制； 2）阐明依赖于STING的信号传导 CGA调节巨噬细胞吞噬作用的机制； 3）探索生理作用 CGAS调节的吞噬作用在预防肝纤维化和NASH方面。我们的研究将剖析新作用 CGA调节巨噬细胞吞噬并防止NASH的机制。综合了解先天免疫和巨噬细胞生物学的基本功能不仅会提供重新思考这种毁灭性肝病的性质的概念证明，但也打开了一种新的治疗方法开发纳什治疗治疗的大道。