The Role of Leptin in Susceptibility to Amebiasis

瘦素在阿米巴病易感性中的作用

• 批准号: 8473656
• 负责人: Chelsea S. Marie
• 金额: $ 5.39万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2015-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8473656
• 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; 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

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.

描述（由申请人提供）：溶作疗法是导致肠道肌动物和阿米比克肝脓肿的致病原生动物。据估计，溶血性大肠杆菌每年会引起5000万感染和100,000人死亡，并且已知营养不良会增加感染的易感性。在营养不良的能量中，细胞因子样激素瘦素降低。最近的证据表明，瘦素是对amebiasis敏感性的关键介体，包括：1）在瘦素受体的细胞外结构域中鉴定多态性（Q223R），可显着提高临床研究中的敏感性； 2）证明Q223R多态性也增加了小鼠的敏感性； 3）发现，肠道上皮的瘦素受体的组织特异性缺失，但在下丘脑中不增加小鼠的敏感性； 4）表明，单细胞中瘦素受体的表达使它们具有抗氨基酸杀伤的体外杀伤。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组织溶解息肉的细胞毒性，但是尚不清楚保护机理。该项目的中心假设是Q223R多态性会导致瘦素受体信号传导，并产生允许对溶组织溶血性大肠杆菌感染的肠上皮。以下目的解决了Q223R多态性的功能以及瘦素信号在细胞对溶液性大肠杆菌敏感性中的作用。特定的目标1将通过测试瘦素受体的结合和/或表面表达来评估Q223R多态性的功能后果，并通过Q223R多态性改变。我们还将测试Q223R多态性是否改变了通过瘦素受体的JAK2，SHP-2，STAT5和STAT3途径的激活。具体目标2将通过细胞对溶液性大肠杆菌的易感性在细胞易感性中通过瘦素受体来确定SHP-2，STAT5和STAT3信号的作用。将通过微阵列分析探索所鉴定的信号通路，并将探索瘦素受体介导的保护的下游效应子。通过评估瘦素受体中单个多态性的特定分子后果，我们将开始描绘粘膜免疫防御的新型机制。这项工作可能对其他肠胃病原体，肠易激病和肠癌的发病机理有影响。此外，对连接营养不良和免疫反应的信号事件的更深入了解将对全球儿童的健康产生积极影响。