Leptin regulation of intestinal inflammation and infection

假设：瘦素是肠道感染炎症反应的重要调节因子，而且确实如此 通过其对肠道的造血细胞或非造血细胞的影响。 瘦素和瘦素受体表达于肠上皮和浸润性单个核细胞。 固有层。瘦素控制上皮钠/糖和多肽转运蛋白的表达， 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)的小鼠已经改变了对 阿米巴病和艰难梭菌，以及实验诱导的炎症性肠病。这些 结果表明，瘦素在肠道感染和炎症中可能具有广泛的调节作用。有趣的是， 一种常见的单一氨基酸(用HapMap分析存在于CephUtah人口的一半中) 瘦素受体(改变其与瘦素的亲和力)的多态性与儿童的抵抗力有关 到阿米巴病，在成年人到阿米巴肝脓肿。我们建议研究瘦素的作用机制 它的受体调节小鼠和人类对感染的肠道防御。首先，我们将测试如何 一般观察瘦素与肠道感染和炎症的关系。通过协作 调查人员将确定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 PAN/URN、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的炎症与骨髓来源细胞的比较 感染剂，以及它对STATS信号的依赖。最后，我们将把这些观察扩展到 通过测试对蓝氏贾第鞭毛虫和肠聚集性大肠杆菌的保护作用与 瘦素受体多态性被发现对阿米巴病具有保护作用。

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.