Role of Dab2 in Fatty Liver Disease

Dab2 在脂肪肝疾病中的作用

• 批准号: 8828681
• 负责人: NORBERT LEITINGER
• 金额: $ 34.37万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-10 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8828681
• 关键词: Acute; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Binding; Biological; Cardiovascular Diseases; Cells; Cirrhosis; Coculture Techniques; Data; Development; Diet; Disabled Homolog 2 Protein; Endotoxemia; Endotoxins; Exposure to; Fatty Liver; Fatty acid glycerol esters; Fibrosis; Foundations; Gene Expression; Goals; Health; Hepatic; Hepatic Tissue; Hepatocyte; Immune response; In Vitro; Individual; Indolent; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Insulin Resistance; Intervention; Knockout Mice; Kupffer Cells; Leukocytes; Link; Liver; Liver diseases; Lymphocyte; Malignant Neoplasms; Metabolic Diseases; Methionine; Methods; Molecular; Molecular Analysis; Mus; Myelogenous; Myeloid Cells; NF-kappa B; NK Cell Activation; Natural Killer Cells; Non obese; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathology; Pathway interactions; Patients; Peripheral; Population; Primary carcinoma of the liver cells; RNA Splicing; Regulation; Resolution; Role; Signal Pathway; Signal Transduction; Staging; Steatohepatitis; T-Lymphocyte; Testing; Translating; Tumor Suppressor Proteins; United States; Variant; Western World; base; cell type; choline deficient diet; chronic liver disease; clinical application; feeding; immunoregulation; in vivo; innovation; insulin sensitivity; interdisciplinary approach; lipid metabolism; liver inflammation; macrophage; mouse model; mutant; non-alcoholic fatty liver; novel; novel strategies; research study; reverse cholesterol transport; screening

DESCRIPTION (provided by applicant): Non alcoholic fatty liver disease (NAFLD) is a major health problem in the United States. It is seen in nonobese and obese patients and accompanied by complications of insulin resistance, type 2 diabetes and cardiovascular disease. Exacerbation of the inflammatory response has been shown to be essential for progression of NAFLD into steatosis, cirrhosis and even hepatocellular carcinoma. Immunoregulation and inflammation are controlled by infiltrating myeloid cells and resident macrophages (Kupffer cells), which regulate activation status of T- cells, NKT cells, NK cells and hepatocytes, all of which are critical for the development of NAFLD. However, the mechanisms that link inflammation to development of NAFLD are poorly understood. Therefore, it is important to identify novel factors and pathways that control the intensity and the duration f the inflammatory response in the liver. Screening for novel regulators of inflammation, we identified disabled homolog 2 (Dab2) as being downregulated in pro-inflammatory M1 and upregulated in anti-inflammatory M2 macrophages. Dab2 is a putative mitogen-responsive phosphoprotein, whose expression is downregulated in various forms of cancer, indicating its role as tumor suppressor. We found that Dab2 binds to components of the NF-kappaB signalling pathway and deletion of Dab2 in myeloid cells in mice resulted in protection of the liver against endotoxemia and high fat diet- induced steatosis. We will test the central hypothesis that myeloid Dab2 is essential for the progression of inflammatory hepatic tissue damage and NAFLD. In a multidisciplinary approach, we will use molecular and cell biological, as well as state of the art immunological methods, lipidomics, and conditional knock out mouse models of endotoxin- and diet- induced liver disease. Specific Aim 1 will test the hypothesis that Dab2 in myeloid-derived cells controls liver inflammation and NAFLD. Specific Aim 2 will determine the mechanistic basis for Dab2-dependent regulation of inflammation and Specific Aim 3 will examine the hypothesis that Dab2 in myeloid cells is essential for cross talk with NK cells in the liver.

描述（由申请人提供）：非酒精性脂肪肝病 (NAFLD) 是美国的一个主要健康问题。常见于非肥胖和肥胖患者，并伴有胰岛素抵抗、2型糖尿病和心血管疾病的并发症。炎症反应的加剧已被证明对于 NAFLD 进展为脂肪变性、肝硬化甚至肝细胞癌至关重要。免疫调节和炎症由浸润性骨髓细胞和常驻巨噬细胞（库普弗细胞）控制，它们调节 T 细胞、NKT 细胞、NK 细胞和肝细胞的激活状态，所有这些对于 NAFLD 的发展都至关重要。然而，人们对炎症与 NAFLD 发展之间的联系机制知之甚少。因此，确定控制肝脏炎症反应强度和持续时间的新因素和途径非常重要。通过筛选新型炎症调节因子，我们发现失能同源物 2 (Dab2) 在促炎性 M1 巨噬细胞中下调，在抗炎性 M2 巨噬细胞中上调。 Dab2 是一种假定的丝裂原反应性磷蛋白，其表达在各种形式的癌症中下调，表明其作为肿瘤抑制因子的作用。我们发现 Dab2 与 NF-kappaB 信号通路的成分结合，小鼠骨髓细胞中 Dab2 的缺失可保护肝脏免受内毒素血症和高脂肪饮食诱导的脂肪变性。 我们将检验这一中心假设：髓样 Dab2 对于炎症性肝组织损伤和 NAFLD 的进展至关重要。在多学科方法中，我们将使用分子和细胞生物学以及最先进的免疫学方法、脂质组学和内毒素和饮食诱导的肝病的条件敲除小鼠模型。具体目标 1 将检验骨髓来源细胞中的 Dab2 控制肝脏炎症和 NAFLD 的假设。具体目标 2 将确定 Dab2 依赖性炎症调节的机制基础，具体目标 3 将检验骨髓细胞中的 Dab2 对于与肝脏中的 NK 细胞的交互至关重要的假设。