Leptin regulation of intestinal inflammation and infection

瘦素对肠道炎症和感染的调节

• 批准号: 7669850
• 负责人: William A Petri
• 金额: $ 31.34万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-03 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7669850
• 关键词: Adult; Affinity; Amebiasis; Amebic Liver Abscess; Amino Acids; Apoptosis; Bone Marrow; Bone Marrow Transplantation; Cells; Child; Clostridium difficile; Cryptosporidium; Cryptosporidium parvum; Dependency; Effector Cell; Entamoeba histolytica; Enteral; Epithelial; Foundations; Genetic Polymorphism; Giardia; Giardia lamblia; Glucose; Hematopoietic; Human; Immune response; Infection; Infectious Agent; Inflammation; Inflammatory Bowel Diseases; Inflammatory Response; Inflammatory disease of the intestine; Intestines; Lamina Propria; Leptin; Leptin receptor mutation; Link; Maryland; Mediating; Modeling; Mononuclear; Mus; Pan Genus; Peptides; Population; Predisposition; Regulation; Research Personnel; Resistance; Role; STAT3 gene; Signal Pathway; Signal Transduction; Sodium; T-Lymphocyte; Testing; Tissues; Universities; Virginia; Work; biodefense; cell type; db/db mouse; enteroaggregative Escherichia coli; intestinal epithelium; leptin receptor; novel; novel strategies; pathogen; programs; receptor; research study; response

Hypothesis: Leptin is an important regulator of the intestinal inflammatory response to infection, and does so through its effects on either hematopoietic or non-hematopoietic cells of the gut. Leptin and leptin receptor are expressed in the intestinal epithelium and in infiltrating mononuclear cells in the lamina propria. Leptin controls expression of epithelial sodium/glucose and peptide transporters, regulates apoptosis, and induces intestinal inflammation via T lymphocytes. We and others have observed that mice deficient in leptin (ob/ob) or functional leptin receptor (db/db) have altered susceptibility to amebiasis and Clostridium difficile, as well as experimentally-induced inflammatory bowel disease. These results suggest that leptin may have broad regulatory roles in enteric infection and inflammation. Intriguingly, a common (present in one half of the CephUtah population analyzed by HapMap) single amino acid polymorphismm in the leptin receptor (that alters its affinity for leptin) is associated with resistance in children to amebiasis, and in adults to amebic liver abscess. We propose to study the mechanisms by which leptin and its receptor regulate intestinal defense against infection in mice and in humans. First we will test how general the observation is of the link of leptin to intestinal infection and inflammation. With collaborating investigators within MARGE we will determine if ob/ob (leptin deficient) and db/db (leptin receptor deficient) mice have increased susceptibility to infection and inflammation due to Giardia lamblia, Cryptospordium pan/urn, enteroaggregative E. coli and C. difficile. We will then determine the contribution to infection and inflammation of leptin and leptin receptor in intestinal epithelium vs. bone marrow-derived cells for a single infectious agent, and its dependency upon STATS signaling. Finally we will extend these observations to humans by testing for associations of protection from Giardia lamblia and enteroaggregative E. coli with the leptin receptor polymorphism found to be protective from amebiasis.

假设：瘦素是肠道对感染的炎症反应的重要调节剂，并且具有这样的作用 通过其对肠道造血或非造血细胞的影响。 瘦素和瘦素受体在肠上皮和浸润性单核细胞中表达 固有层。瘦素控制上皮钠/葡萄糖和肽转运蛋白的表达， 调节细胞凋亡，并通过 T 淋巴细胞诱导肠道炎症。我们和其他人观察到 缺乏瘦素 (ob/ob) 或功能性瘦素受体 (db/db) 的小鼠会改变对 阿米巴病和艰难梭菌，以及实验诱发的炎症性肠病。这些 结果表明瘦素可能在肠道感染和炎症中具有广泛的调节作用。有趣的是， 一种常见的（存在于 HapMap 分析的 CephUtah 群体的一半中）单一氨基酸 瘦素受体的多态性（改变其对瘦素的亲和力）与儿童的抵抗力有关 导致阿米巴病，成人则导致阿米巴肝脓肿。我们建议研究瘦素的机制 其受体调节小鼠和人类肠道防御感染的能力。首先我们将测试如何 一般来说，观察结果是瘦素与肠道感染和炎症之间的联系。与合作 MARGE 内的研究人员将确定是否有 ob/ob（瘦素缺乏）和 db/db（瘦素受体缺乏） 小鼠对蓝氏贾第鞭毛虫、隐孢子虫感染和炎症的易感性增加 盘/瓮，肠聚集性大肠杆菌和艰难梭菌。然后我们将确定对感染的贡献和 肠上皮中瘦素和瘦素受体与骨髓来源细胞的炎症反应 传染原及其对 STATS 信号传导的依赖性。最后我们将把这些观察扩展到 通过测试对兰氏贾第鞭毛虫和肠聚集性大肠杆菌的保护作用与人类 瘦素受体多态性被发现可以预防阿米巴病。