Tuft cells in intestinal homeostasis

描述(申请人提供)：肠道含有数以万亿计的微生物，这些微生物增强新陈代谢能力，促进免疫细胞发育，并限制入侵病原体的定居。然而，这种微生物群落的紊乱可能导致严重的健康挑战，如炎症性肠道疾病、1型糖尿病和肥胖症。肠道上皮与微生物区系持续接触，对维持肠道是必不可少的。 动态平衡。通常，肠上皮被描述为由四个细胞亚群组成，但最近的证据表明，簇状细胞代表第五种上皮细胞类型。虽然簇状细胞最早是在1955年被描述的，但直到最近才有工具和特定的标记物可以明确地将这些细胞与其余的上皮细胞区分开来。人们对丛生细胞生理学知之甚少，它们与微生物区系的关系也完全没有被探索过。丛生细胞表达以味觉功能著称的关键味觉成分。然而，有证据表明，味觉感受器可以对微生物做出反应。这项提议将确定丛生细胞上表达的特定味觉受体和刺激它们的微生物配体。簇状细胞味觉信号的一个结果可能是肠道固有层T细胞发育的改变。这将使用体外T细胞发育试验进行测试，并在小鼠身上得到验证。这项研究的最终目标将确定丛生细胞对小鼠结肠炎模型的更广泛影响。这项建议中描述的实验将使人们更好地理解丛生细胞、免疫系统和微生物之间的复杂关系。丛生细胞是宿主-微生物区系相互作用的全新参与者；因此，这些研究可能扩大治疗胃肠道炎症性疾病的选择。

DESCRIPTION (provided by applicant): The gut contains trillions of microbes that enhance metabolic capability, promote immune cell development, and limit colonization by invading pathogens. However, disturbance of this microbial community can lead to serious health challenges such as inflammatory bowel disease, type 1 diabetes, and obesity. The gut epithelium is in continuous contact with the microbiota and is essential for maintaining intestinal homeostasis. Commonly, the intestinal epithelium is described as consisting of four cell subsets, but recent evidence suggests that tuft cells represent a fifth epithelial cell type. Though tuft cels were first described in 1955, only recently have the tools and specific markers become available to unambiguously identify these cells from the rest of the epithelium. Very little is known about tuft cell physiology and their relationship to the microbiota is completely unexplored. Tuft cells express key taste components that are known for their gustatory function. However there is evidence that taste receptors can respond to microbes. This proposal will identify the specific taste receptors expressed on tuft cells and the microbial ligands that stimulate them. One consequence of tuft cell taste signaling may be the alteration of T cell development in the intestinal lamina propria. This will be tested using an in vitro T cell development assays and be verified in the mouse. The final aim of this fellowship will determine the broader impact of tuft cells on mouse models of colitis. The experiments described in this proposal will lead to an enhanced understanding of the complex relationship between the tuft cells, the immune system, and microorganisms. Tuft cells are completely novel participants in the host-microbiota interaction; consequently these studies may expand therapeutic options to treat gastrointestinal inflammatory disease.