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

• 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
• 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' 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

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 屏障并积极分泌粘液和抗微生物肽。肠上皮由 通过细胞分裂，分化和细胞凋亡的循环的恒定更新的过程。凋亡是 调节性CD4 T（Treg）细胞和免疫耐受性的有效诱导剂。在感染期间，凋亡诱导A 量身定制的CD4 T助手17（TH17）响应。肠上皮细胞（IEC）的凋亡是否起任何作用 在肠道耐受性和效应子反应中尚不清楚。专业的单核吞噬细胞（MP），这样 作为巨噬细胞和树突状细胞（DC），在感染期间清除微生物病原体和凋亡细胞。 胚胎发育和组织重塑。虽然很多关注集中在MP采样 肠道内的共生和致病微生物，较少的注意力用于采样 凋亡IEC的凋亡作用在肠上皮中起着重要作用。干扰 IEC中凋亡的自然循环导致小鼠模型中的肠炎。 IEC增加了 炎症性肠病（IBD）患者肠上皮的死亡和损害，这燃料 肠道疾病和炎症。几项国际IBD基因组广泛协会研究（GWAS）和 荟萃分析对IBD的敏感性与调节先天免疫的途径有关 反应，免疫调节细胞因子和TH17信号传导。来自不同鼠细胞的基因表达数据 类型显示，先天性免疫细胞，尤其是DC中IBD基因的富集最强。获得一个 了解肠上皮的凋亡是否以及如何影响耐受性的过程 因此，肠内的免疫力至关重要。 使用两个新型的小鼠模型，我们将确定如何增加或损害凋亡的凋亡 肠上皮影响肠内的稳态和免疫反应。我们很有说服力 小肠上皮中凋亡的证据不是旁观者事件，而是积极印记。 具有“抑制炎症”和“ Treg细胞诱导”转录特征的Propria MP。尤其， 凋亡IEC摄取与IBD基因重叠后，许多基因在MP中差异化。我们在这里 将检查在稳态和感染期间结肠MP的身份和特征。我们将调查如何 凋亡会影响肠道MP的功能，因为它们与免疫耐受性的各种机制有关 和肠中的效应子响应。这包括他们对微生物组件的反应，维护 先天性淋巴样细胞的及其Treg和Th17细胞命运的指导。所有这些参数都在中断 IBD。通过完成这些研究，我们将获得对凋亡在肠道中的作用的新见解 免疫调节，提高我们对粘膜内稳态如何保持的理解，并设定 炎症性疾病（例如IBD）开发新型治疗剂的阶段。