The Role of Leptin in Susceptibility to Amebiasis

描述（由申请方提供）：溶组织内阿米巴是引起肠道阿米巴病和阿米巴肝脓肿的致病性原生动物。E.据估计，溶组织菌每年造成5 000万人感染和10万人死亡，而且已知营养不良会增加感染的易感性。类瘦素激素减少的能量营养不良。最近的证据表明瘦素是阿米巴病易感性的关键介质，包括：1）在临床研究中，瘦素受体胞外结构域的多态性（Q223 R）显著增加易感性的鉴定; 2）证明Q223 R多态性也增加小鼠的易感性; 3）发现在肠上皮组织特异性缺失瘦素受体，而不是在下丘脑，增加小鼠的易感性;和4）证明单细胞中瘦素受体的表达使它们在体外对阿米巴杀伤具有抵抗力。这些数据共同表明瘦素信号直接保护肠上皮细胞免受E.然而，保护机制尚不清楚。该项目的中心假设是Q223 R多态性使瘦素受体信号转导失调，并产生了允许E.溶组织感染下面的目的是阐明Q223 R多态性的功能和瘦素信号在细胞对大肠杆菌易感性中的作用。溶组织剂具体目标1将通过测试瘦素结合和/或瘦素受体的表面表达是否被Q223 R多态性改变来评估Q223 R多态性的功能后果。我们还将测试Q223 R多态性是否通过瘦素受体改变JAK 2、SHP-2、STAT 5和STAT 3通路的激活。具体目标2将确定SHP-2、STAT 5和STAT 3信号通过瘦素受体在细胞对E.溶组织剂将验证所确定的信号通路，并通过微阵列分析探索瘦素受体介导的保护的下游效应物。通过评估瘦素受体单一多态性的特定分子后果，我们将开始描绘一种新的粘膜免疫防御机制。这项工作可能对其他肠道病原体，肠易激综合征和肠癌的发病机制有影响。此外，更好地了解将营养不良和免疫反应联系起来的信号事件将对全世界儿童的健康产生积极影响。 公共卫生相关性：这项研究将评估与儿童阿米巴病易感性密切相关的瘦素受体单一多态性的特定分子后果。更好地理解连接营养和阿米巴病免疫反应的信号事件将对全世界儿童的健康产生积极影响。

DESCRIPTION (provided by applicant): Entamoeba histolytica is the pathogenic protozoan responsible for intestinal amebiasis and amebic liver abscess. E. histolytica is estimated to cause 50 million infections and 100,000 deaths annually and malnutrition is known to increase susceptibility to infection. The cytokine-like hormone leptin is reduced in the energy malnourished. Recent evidence that leptin is a pivotal mediator of susceptibility to amebiasis includes: 1) the identification of a polymorphism (Q223R) in the extracellular domain of the leptin receptor that significantly increases susceptibility in clinical studies; 2) demonstration that the Q223R polymorphism also increases susceptibility in mice; 3) the finding that tissue-specific deletion of the leptin receptor at the intestinal epithelium, but not in the hypothalamus, increases susceptibility in mice; and 4) demonstration that expression of the leptin receptor in single cells renders them resistant to amebic killing in vitro. Together these data indicate that leptin signaling directly protects intestinal epithelial cells from E. histolytica cytotoxicity, however the mechanism of protection is not understood. The central hypothesis of this project is that the Q223R polymorphism deregulates leptin receptor signaling and creates an intestinal epithelium that is permissive to E. histolytica infection. The following aims address the function of the Q223R polymorphism and the role of leptin signaling in cellular susceptibility to E. histolytica. Specific aim 1 will evaluate the functional consequences of the Q223R polymorphism by testing if leptin binding and/or surface expression of the leptin receptor is altered by the Q223R polymorphism. We will also test if the Q223R polymorphism alters activation of JAK2, SHP-2, STAT5 and STAT3 pathways through the leptin receptor. Specific aim 2 will determine the role of SHP-2, STAT5 and STAT3 signaling through the leptin receptor in cellular susceptibility to E. histolytica. The signaling pathway identified will be validated and downstream effectors of leptin receptor-mediated protection will be explored by microarray analysis. By evaluating the specific molecular consequences of a single polymorphism in the leptin receptor, we will begin to delineate a novel mechanism of mucosal immune defense. This work may have implications for the pathogenesis of other enteric pathogens, irritable bowel disease and intestinal cancer. Additionally, a greater understanding of the signaling events that connect malnutrition and the immune response will positively impact the health of children worldwide. PUBLIC HEALTH RELEVANCE: This research will evaluate the specific molecular consequences of a single polymorphism in the leptin receptor that is strongly associated with susceptibility to amebiasis in children. A greater understanding of the signaling events that connect nutrition and the immune response to amebiasis will positively impact the health of children worldwide.