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， 通过其对肠道的造血或非造血细胞的作用。 瘦素和瘦素受体表达于肠上皮细胞和浸润的单核细胞中， 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（存在于通过HapMap分析的一半CephUtah人群中）单一氨基酸 瘦素受体的多态性（改变其对瘦素的亲和力）与儿童的抵抗有关 阿米巴病，成人阿米巴肝脓肿。我们建议研究瘦素的机制， 及其受体调节小鼠和人类肠道对感染的防御。首先我们将测试如何 总的来说，观察到瘦素与肠道感染和炎症的联系。与各协作 MARGE内的研究人员将确定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 pan/urn，肠聚集性E.大肠杆菌和C.很难然后我们将确定对感染的贡献， 瘦素和瘦素受体在肠上皮细胞与骨髓来源细胞中的炎症 感染因子及其对STATS信号传导的依赖性。最后，我们将这些观察扩展到 通过检测对蓝氏贾第鞭毛虫和肠聚集性E.大肠杆菌， 瘦素受体多态性对阿米巴病有保护作用

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.