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: 10048223
• 负责人: Ken S Lau
• 金额: $ 59.74万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10048223
• 关键词: Ablation; Affect; Antigens; Architecture; Biological Assay; Cell Lineage; Cells; Cellular biology; Chemical Models; Chemicals; Complementary therapies; Complex; Computer Analysis; Country; Crohn' s disease; Cytometry; Dependence; Developed Countries; Diagnosis; Disease; Disease model; Electron Microscopy; Enzyme-Linked Immunosorbent Assay; Epithelial; Fluorescence; Genetic; Genetic Models; Goals; Heterogeneity; Human; Hygiene; Ileal Diseases; Image Cytometry; Immune; Immune response; Immune system; Immunofluorescence Microscopy; Incidence; Individual; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Intestinal Mucosa; Intestines; Knowledge; Microscopy; Modeling; Mucous Membrane; Mus; Organ; Organoids; PTGS2 gene; Parasites; Parasitic Diseases; Parasitic infection; Pathway interactions; Patients; Population; Population Heterogeneity; Precision therapeutics; Research; Resolution; Rest; Role; Rosaniline Dyes; Sampling; Sentinel; Small Intestines; Sorting - Cell Movement; Specimen; Stains; Structure; Structure-Activity Relationship; Testing; Therapeutic; Time; Tissues; Work; cell type; cytokine; design; disorder subtype; genetic manipulation; helminth infection; host microbiome; immunoregulation; in vivo Model; innovation; longitudinal analysis; microbiome; microbiota; mouse model; multiplexed imaging; novel; patient stratification; response; single cell sequencing; single-cell RNA sequencing; therapeutic target; transcription factor; tumor-immune system interactions

PROJECT SUMMARY/ABSTRACT Inflammatory Bowel Disease (IBD) and its subtype Crohn’s disease (CD) arise due to a loss of tolerance to environmental antigens in genetically susceptible individuals. Longitudinal analysis has identified an inverse correlation between rates of communicable parasitic diseases and IBD, a phenomenon termed the “hygiene hypothesis.” Tuft cells have recently been identified as a critical component for sensing and responding to parasitic infections. Our lab has recently identified that tuft cells may be heterogeneous in their lineage and function in microbiome response, and specific populations may be critical for mitigating inflammation in ileal inflammatory disease. Here, we propose innovative experimental and computational approaches to dissect the heterogeneity of tuft cell lineage, structure, and function as they relate to regulating immune responses in in vivo models of CD. In aim 1, we will conduct single-cell sequencing, high resolution microscopy, and functional secretory assays to understand lineage-structure-function relationships in different tuft cell populations in mouse and enteroid models. In aim 2, we utilize multiplex imaging, Cytometry Time-of-Flight (CyTOF), and cytokine profiling to probe the downstream tuft-type 2 response network by utilizing several chemical and genetic models of pathway ablation. Through our findings, we aim to make significant contributions to the current understanding of tuft cell biology and epithelial-microbiome crosstalk in the intestine. Ultimately, this research will allow us to diagnose, stratify, and, ultimately, treat patients with IBD and expand the pool of targets in this complex, multifactorial disease.

项目概要/摘要 炎症性肠病 (IBD) 及其亚型克罗恩病 (CD) 是由于 遗传易感个体对环境抗原的耐受性的纵向分析。 已经确定传染性寄生虫病的发病率与 IBD 之间呈负相关， 一种被称为“卫生假说”的现象最近被确定为 我们的实验室最近发现了感知和响应寄生虫感染的关键成分。 发现簇细胞的谱系和微生物组功能可能存在异质性 反应和特定人群可能对于减轻回肠炎症至关重要 在这里，我们提出了创新的实验和计算方法来剖析疾病。 簇细胞谱系、结构和功能的异质性，因为它们与调节免疫有关 CD 体内模型中的反应在目标 1 中，我们将进行单细胞测序，高。 分辨率显微镜和功能分泌测定以了解谱系-结构-功能 在目标 2 中，我们利用 多重成像、细胞飞行时间 (CyTOF) 和细胞因子分析来探测 下游簇2型反应网络利用多种化学和遗传模型 通过我们的研究结果，我们的目标是为当前的研究做出重大贡献。 了解肠道中的簇细胞生物学和上皮微生物组串扰。 这项研究将使我们能够诊断、分层并最终治疗 IBD 患者，并扩大 这种复杂、多因素疾病的靶标库。