Tuft cells in intestinal homeostasis

描述（由申请人提供）：肠道含有数万亿微生物，可增强代谢能力，促进免疫细胞发育，并限制入侵病原体的定植。然而，这种微生物群落的紊乱可能导致严重的健康挑战，如炎症性肠病，1型糖尿病和肥胖症。肠道上皮细胞与微生物群持续接触，对于维持肠道功能至关重要。 体内平衡通常，肠上皮被描述为由四种细胞亚群组成，但最近的证据表明，簇状细胞代表第五种上皮细胞类型。虽然簇状上皮细胞在1955年首次被描述，但直到最近才有工具和特异性标记物可以明确地将这些细胞与上皮的其余部分区分开来。关于簇细胞生理学知之甚少，它们与微生物群的关系完全未被探索。毛簇细胞表达以味觉功能而闻名的关键味觉成分。然而，有证据表明味觉受体可以对微生物做出反应。这项建议将确定特定的味觉受体表达的簇细胞和微生物的配体，刺激他们。毛簇细胞味觉信号传导的一个结果可能是肠固有层中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，并在小鼠中进行验证。这项研究的最终目的将确定簇细胞对结肠炎小鼠模型的更广泛影响。本提案中描述的实验将导致对簇细胞，免疫系统和微生物之间复杂关系的进一步理解。簇细胞是宿主-微生物群相互作用的全新参与者;因此，这些研究可能会扩大治疗胃肠道炎症性疾病的治疗选择。

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.