The Role of Leptin in Susceptibility to Amebiasis

瘦素在阿米巴病易感性中的作用

基本信息

批准号：
8057481
负责人：
Chelsea S. Marie
金额：
$ 5.13万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8057481
关键词：
Address Affinity Amebiasis Amebic Liver Abscess Amebic colitis Amino Acid Substitution Area Binding Biological Assay Cell Line Cells Cessation of life Child Child health care Clinical Research Communicable Diseases Cytoplasmic Tail Data Development Disease Disease susceptibility Dominant-Negative Mutation Entamoeba histolytica Epithelial Cells Event Extracellular Domain Flow Cytometry Genetic Genetic Polymorphism Hormones Hypothalamic structure Immune Immune response Immunologic Factors In Vitro Infection Intestinal Cancer Intestines JAK2 gene Leptin Malnutrition Mediating Mediator of activation protein Metabolic Diseases Microarray Analysis Molecular Mucosal Immune Responses Mus PTPN11 gene Pathogenesis Pathway interactions Predisposition Receptor Signaling Research Resistance Role STAT3 gene STAT5A gene Signal Pathway Signal Transduction Surface Testing Tissues Tyrosine Vaccines Work cytokine cytotoxicity effective therapy enteric pathogen global health inhibitor/antagonist intestinal epithelium killings leptin receptor novel nutrition small hairpin RNA

项目摘要

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.

描述（由申请人提供）：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原虫。据估计，溶组织内阿米巴每年导致 5000 万人感染和 10 万人死亡，而营养不良会增加感染的易感性。细胞因子样激素瘦素在能量营养不良时减少。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，瘦素受体胞外域的多态性（Q223R）的鉴定显着增加了易感性； 2) 证明Q223R多态性也增加小鼠的易感性； 3）发现肠上皮（而非下丘脑）的瘦素受体的组织特异性缺失会增加小鼠的易感性； 4) 证明单细胞中瘦素受体的表达使其能够抵抗体外阿米巴杀伤作用。这些数据共同表明，瘦素信号传导直接保护肠上皮细胞免受溶组织内阿米巴细胞毒性的影响，但保护机制尚不清楚。该项目的中心假设是，Q223R 多态性解除了瘦素受体信号传导的调节，并产生了允许溶组织内阿米巴感染的肠上皮。以下目标探讨 Q223R 多态性的功能以及瘦素信号在细胞对溶组织内阿米巴易感性中的作用。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Q223R多态性改变来评估Q223R多态性的功能后果。我们还将测试 Q223R 多态性是否通过瘦素受体改变 JAK2、SHP-2、STAT5 和 STAT3 通路的激活。具体目标 2 将确定 SHP-2、STAT5 和 STAT3 通过瘦素受体信号传导在细胞对溶组织内阿米巴易感性中的作用。将验证确定的信号通路，并通过微阵列分析探索瘦素受体介导的保护的下游效应器。通过评估瘦素受体单一多态性的具体分子后果，我们将开始描绘粘膜免疫防御的新机制。这项工作可能对其他肠道病原体、肠易激病和肠癌的发病机制有影响。此外，更好地了解营养不良和免疫反应之间的信号事件将对全世界儿童的健康产生积极影响。公共健康相关性：这项研究将评估瘦素受体单一多态性的具体分子后果，该多态性与儿童阿米巴病的易感性密切相关。更好地了解将营养和阿米巴病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。