Role of Dab2 in Fatty Liver Disease

描述（由申请人提供）：非酒精性脂肪肝（NAFLD）是美国的一个主要健康问题。它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。炎症反应的加重已被证明是NAFLD进展为脂肪变性、肝硬化甚至肝细胞癌的关键。免疫调节和炎症由浸润的骨髓细胞和驻留的巨噬细胞（枯否细胞）控制，其调节T细胞、NKT细胞、NK细胞和肝细胞的活化状态，所有这些对于NAFLD的发展都是关键的。然而，将炎症与NAFLD发展联系起来的机制知之甚少。因此，重要的是要确定控制肝脏炎症反应强度和持续时间的新因素和途径。筛选新的炎症调节因子，我们鉴定出失能同源物2（Dab 2）在促炎性M1中下调，在抗炎性M2巨噬细胞中上调。Dab 2是一种假定的促分裂原反应磷蛋白，其表达在各种形式的癌症中下调，表明其作为肿瘤抑制剂的作用。我们发现Dab 2与NF-κ B信号传导途径的组分结合，并且小鼠骨髓细胞中Dab 2的缺失导致保护肝脏免受内毒素血症和高脂饮食诱导的脂肪变性。 我们将检验髓样Dab 2对炎性肝组织损伤和NAFLD的进展至关重要的中心假设。在多学科的方法中，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性敲除小鼠模型。特异性目的1将检验骨髓源性细胞中的Dab 2控制肝脏炎症和NAFLD的假设。具体目标2将确定Dab 2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Dab 2对于与肝脏中NK细胞的串扰至关重要的假设。

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.