Tuft cell heterogeneity in function, lineage, and structure in ileal inflammatory disease

回肠炎症性疾病中簇细胞功能、谱系和结构的异质性

• 批准号: 10396926
• 负责人: Ken S Lau
• 金额: $ 4.72万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10396926
• 关键词: Ablation; Architecture; Biological Assay; Cells; Cellular biology; Complex; Crohn' s disease; Disease; Epithelial; Heterogeneity; Immune response; Immunofluorescence Immunologic; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Injury; Intestinal Diseases; Intestines; Microbe; Mucous Membrane; Prostaglandin Production; Prostaglandins; Research; Role; Structure; Therapeutic; Ulcerative Colitis; experimental study; immunoregulation; inflammatory disease of the intestine; innovation; knockout gene; microbiome; mouse model; novel; restoration; single cell sequencing

PROJECT SUMMARY/ABSTRACT Inflammatory bowel disease (IBD), such as Crohn’s disease (CD) and ulcerative colitis (UC), is a complex group of intestinal disorders that results in injury to the epithelium exposing the host to the luminal microbes. Tuft cells have recently been identified as a responder to the microbiome, where they can secrete damage-restitution molecules such as prostaglandins. Furthermore, our lab has successfully demonstrated that tuft cells promote the restoration of intestinal architecture in ileal inflammatory disease. In this supplement, we propose innovative experimental and computational approaches to decipher the effector molecules downstream of tuft cells that modulate inflammation. We will use mouse models where of tuft cell ablation and tuft cell specific gene knockout to determine whether prostaglandin production from tuft cells is responsible for their immunomodulatory effects. The epithelial and microenvironmental mechanisms responsible for these changes will be assayed by single-cell sequencing and multiplex immunofluorescence. Through our findings, we aim to make significant contributions to the current understanding of tuft cell biology and inflammation in the intestine. Ultimately, this research will allow us to better understand where tuft cells act in IBD and expand the pool of targets in this complex, multifactorial disease.

项目概要/摘要 炎症性肠病 (IBD)，例如克罗恩病 (CD) 和溃疡性结肠炎 (UC)，是一种 一组复杂的肠道疾病，导致上皮损伤，使宿主暴露于 管腔微生物最近被确定为微生物群的反应者， 它们可以分泌损伤恢复分子，例如前列腺素。 实验室已成功证明簇细胞促进肠道结构的恢复 在本补充品中，我们提出了创新的实验和方法。 破译簇细胞下游效应分子的计算方法 我们将使用簇细胞消融和簇细胞特异性的小鼠模型。 基因敲除以确定簇细胞产生前列腺素是否是造成这种情况的原因 它们的免疫调节作用是由上皮和微环境机制决定的。 这些变化将通过单细胞测序和多重免疫荧光进行检测。 通过我们的发现，我们的目标是为当前对簇绒的理解做出重大贡献 最终，这项研究将使我们能够更好地了解肠道的细胞生物学和炎症。 了解簇细胞在 IBD 中的作用并扩大这个复杂、多因素的靶标库 疾病。