Role of Dab2 in Fatty Liver Disease

描述(申请人提供)：非酒精性脂肪性肝病(NAFLD)在美国是一个主要的健康问题。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。炎症反应的加剧是NAFLD进展为脂肪变性、肝硬变甚至肝细胞癌的关键。免疫调节和炎症是由浸润的髓系细胞和常驻巨噬细胞(Kupffer细胞)控制的，它们调节T细胞、NKT细胞、NK细胞和肝细胞的激活状态，这些细胞都对NAFLD的发展至关重要。然而，炎症与NAFLD发展之间的联系机制却知之甚少。因此，确定控制肝脏炎症反应强度和持续时间的新因素和新途径是很重要的。在筛选新的炎症调节因子时，我们发现禁用的同系物2(DAB2)在促炎症的M1中下调，在抗炎的M2巨噬细胞中上调。DAB2是一种可能的有丝分裂原反应性磷酸蛋白，在各种形式的癌症中表达下调，表明其作为肿瘤抑制因子的作用。我们发现DAB2与核因子-kappaB信号通路的组成部分结合，并在小鼠髓系细胞中缺失DAB2，从而保护肝脏免受内毒素血症和高脂饮食诱导的脂肪变性的影响。我们将验证中心假设，即髓系DAB2在炎性肝组织损伤和NAFLD的进展中是必不可少的。在一个多学科的方法中，我们将使用分子和细胞生物学，以及最新的免疫学方法，脂质组学，以及内毒素和饮食诱导的肝病的条件性基因敲除小鼠模型。特定目标1将测试髓系细胞中的DAB2控制肝脏炎症和NAFLD的假设。特异性目标2将确定DAB2依赖的炎症调节的机制基础，特异性目标3将检验髓系细胞中的DAB2对于肝脏中NK细胞的串扰是必不可少的假说。

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.