Role of apoptosis in the intestinal epithelium during homeostasis and disease

肠上皮细胞凋亡在稳态和疾病过程中的作用

基本信息

批准号：
9926879
负责人：
Julie Magarian Blander
金额：
$ 38.14万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9926879
关键词：
Abnormal Cell Acute Anti-Inflammatory Agents Apoptosis Apoptotic Attention Autophagocytosis BAX gene Biological CASP8 gene Cell Cycle Cell Death Cell Differentiation process Cell physiology Cells Cessation of life Chimeric Proteins Chronic Complex Crohn&apos s disease Data Dendritic Cells Development Disease Distal part of ileum Embryonic Development Epithelial Cells Event Frequencies Gene Expression Gene Expression Profile Genes Genetic Transcription Homeostasis ITGAM gene Immune Immune Tolerance Immune response Immunity Impairment Infection Inflammation Inflammatory Inflammatory Bowel Diseases Innate Immune Response Instruction International Intestines Lamina Propria Large Intestine Ligands Lymphoid Cell Maintenance Meta-Analysis Mitochondrial Proteins Mononuclear Mucosal Immune Responses Mucous Membrane Mucous body substance Mus Mutant Strains Mice Necrosis Paneth Cells Pathogenicity Pathology Pathway interactions Patients Phagocytes Phagocytosis Phosphotransferases Play Predisposition Process RIPK3 gene Role Sampling Serous Membrane Signal Transduction Single Nucleotide Polymorphism Small Intestines Susceptibility Gene T cell differentiation TNF gene Terminal Ileitis Tissues Tumor Necrosis Factor Receptor Virulence Factors XBP1 gene antimicrobial peptide biological adaptation to stress cell injury cell type cytokine design dextran sulfate sodium induced colitis differential expression diphtheria toxin receptor embryo tissue endoplasmic reticulum stress enteric pathogen epithelial injury food antigen genome wide association study high risk immune function immunoregulation imprint inflammatory disease of the intestine innate immune function insight interest intestinal epithelium intestinal homeostasis macrophage mesenteric lymph node microbial microbiota microorganism mouse model novel novel therapeutics pathogen pathogenic microbe programs response self-renewal transcriptome uptake

项目摘要

PROPOSAL SUMMARY The intestinal epithelium protects against food antigens and the luminal microbiota by forming a physical barrier and actively secreting mucous and anti-microbial peptides. The intestinal epithelium is maintained by a process of constant renewal through a cycle of cell division, differentiation, and apoptosis. Apoptosis is a potent inducer of regulatory CD4 T (TREG) cells and immune tolerance. During infection, apoptosis induces a tailored CD4 T helper 17 (TH17) response. Whether apoptosis of intestinal epithelial cells (IEC) plays any role in intestinal tolerance and effector response is not known. Professional mononuclear phagocytes (MP), such as macrophages and dendritic cells (DC), clear microbial pathogens during infection and apoptotic cells during embryonic development and tissue remodeling. While much attention has centered on MP sampling of commensal and pathogenic microorganisms within the gut lumen, less attention is directed towards sampling of apoptotic IEC, despite the prominent role that apoptosis plays in the intestinal epithelium. Interference with the natural cycle of apoptosis in IEC leads to intestinal inflammation in mouse models. There is increased IEC death and damage to the intestinal epithelium in patients with inflammatory bowel disease (IBD), and this fuels intestinal dybsiosis and inflammation. Several international IBD genome wide association studies (GWAS) and meta-analyses have associated susceptibility to IBD with genes involved in pathways regulating innate immune responses, immunomodulatory cytokines, and TH17 signaling. Gene expression data from different murine cell types have shown the strongest enrichment of IBD genes in innate immune cells, particularly DC. Gaining an understanding of whether and how apoptosis of the intestinal epithelium impacts the processes of tolerance and immunity within the intestine is therefore of utmost importance. Using two novel mouse models, we will determine how increasing or impairing apoptosis of the intestinal epithelium impacts the homeostatic and immune responses within the intestine. We have compelling evidence that apoptosis in the small intestinal epithelium is not a bystander event, but actively imprints lamina propria MP with `suppression of inflammation' and `induction of TREG cell' transcriptional signatures. Notably, many of the genes differentially modulated in MP after apoptotic IEC uptake overlap with IBD genes. Here we will examine the identities and profiles of colonic MP during steady state and infection. We will investigate how apoptosis impacts the functions of intestinal MP as they relate to various mechanisms of immune tolerance and effector response in the intestine. This includes their response to microbial components, their maintenance of innate lymphoid cells, and their instruction of TREG and TH17 cell fates. All these parameters are disrupted in IBD. By the completion of these studies, we will have gained new insights into the role of apoptosis in intestinal immune regulation, advance our understanding of how homeostasis is maintained within the mucosa, and set the stage for development of novel therapeutics for inflammatory diseases such as IBD.

提案摘要肠上皮通过形成物理结构来防御食物抗原和肠腔微生物群。屏障并积极分泌粘液和抗微生物肽。肠上皮由以下物质维持通过细胞分裂、分化和凋亡循环不断更新的过程。细胞凋亡是一种调节性 CD4 T (TREG) 细胞和免疫耐受的有效诱导剂。在感染过程中，细胞凋亡会诱导定制的 CD4 T 辅助细胞 17 (TH17) 反应。肠上皮细胞凋亡（IEC）是否发挥作用肠道耐受性和效应反应尚不清楚。专业单核吞噬细胞（MP），例如作为巨噬细胞和树突状细胞（DC），在感染过程中清除微生物病原体，在感染过程中清除凋亡细胞胚胎发育和组织重塑。虽然很多注意力都集中在 MP 采样上肠腔内的共生微生物和病原微生物，较少关注采样尽管细胞凋亡在肠上皮细胞中发挥着重要作用，但细胞凋亡的 IEC 仍然存在。干扰 IEC 中细胞凋亡的自然循环会导致小鼠模型肠道炎症。 IEC 增加炎症性肠病（IBD）患者的死亡和肠上皮损伤，这加剧了肠道菌群失调和炎症。多项国际 IBD 全基因组关联研究 (GWAS) 和荟萃分析将 IBD 易感性与调节先天免疫途径的基因相关联反应、免疫调节细胞因子和 TH17 信号传导。来自不同小鼠细胞的基因表达数据类型显示出先天免疫细胞（尤其是 DC）中 IBD 基因的最强富集。获得了解肠上皮细胞凋亡是否以及如何影响耐受过程因此，肠道内的免疫力至关重要。使用两种新的小鼠模型，我们将确定如何增加或削弱细胞凋亡肠上皮影响肠道内的稳态和免疫反应。我们有令人信服的有证据表明小肠上皮细胞凋亡不是旁观者事件，而是主动印记层 propria MP 具有“抑制炎症”和“诱导 TREG 细胞”转录特征。尤其，凋亡性 IEC 摄取后 MP 中差异调节的许多基因与 IBD 基因重叠。在这里我们将检查稳态和感染期间结肠 MP 的身份和概况。我们将调查如何细胞凋亡影响肠道 MP 的功能，因为它们与多种免疫耐受机制有关和肠道内的效应器反应。这包括它们对微生物成分的反应、它们的维护先天淋巴细胞的结构，及其对 TREG 和 TH17 细胞命运的指导。所有这些参数都被打乱炎症性肠病。通过完成这些研究，我们将对细胞凋亡在肠道中的作用有新的认识。免疫调节，增进我们对如何维持粘膜内稳态的理解，并设定 IBD 等炎症性疾病新疗法的开发阶段。