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Regulation of intestinal tissue homeostasis by the transcription factor Escargot

转录因子蜗牛对肠道组织稳态的调节

基本信息

批准号：
9124684
负责人：
Hyun Chul Choi
金额：
$ 6万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9124684
关键词：
Adult Age Age of Onset Aging Animals Apical Binding Biological Assay Bleomycin CDH13 gene CRISPR/Cas technology Cell Adhesion Cell Adhesion Molecules Cell Differentiation process Cell Proliferation Cell-Cell Adhesion Cells Cellular biology Chromatin Complex Data Daughter Degenerative Disorder Development Drosophila genus Drosophila inturned protein Drosophila melanogaster E-Cadherin Enterocytes Enteroendocrine Cell Environment Epithelial Epithelial Cells Epitopes Equilibrium Family Fluorescent in Situ Hybridization Functional disorder Gene Expression Gene Targeting Genes Genetic Epistasis Genetic Transcription Genome Health Homeostasis Infection Inflammation Insecta Intercellular Junctions Intestinal Intraepithelial Neoplasia Intestines Intrinsic factor Ions Knowledge Lead Life Maintenance Malignant Neoplasms Mammals Mediating Mesenchymal Messenger RNA Microbe Natural regeneration Neoplasm Metastasis Organ Organism Pathway interactions Permeability Phenotype Physiological Polyploidy Population Proliferating Proteins Regenerative Medicine Regulation Reporter Repression Risk Factors Role Secretory Cell Septate Signal Pathway Signal Transduction Snails Sorting - Cell Movement Stem cells Stress Surface Testing Tight Junctions Time Tissues Toxin aged analog cancer initiation cell behavior cell type daughter cell environmental change feeding fly in vivo insight intestinal epithelium intestinal homeostasis juvenile animal knock-down macromolecule member organ regeneration overexpression programs promoter protein expression public health relevance response self-renewal stem stem cell biology trait transcription factor transcriptome transcriptome sequencing tumor progression tumorigenesis water flow

项目摘要

DESCRIPTION (provided by applicant): A remarkable trait of all organisms is their ability to adjust to the changes in the surrounding environment, and a similar degree of plasticity is observed at the levels of cells and tissues. In the intestine of adult Drosophila melanogaster, intestinal stem cells (ISCs) proliferate and differentiate to maintain the populations of absorptiv and secretory cells that comprise the organ. However, the balance between proliferation and differentiation is tipped by external insults such as damage, inflammation, or aging, resulting in an uncontrolled proliferation of stem cells, an accumulation of mis-differentiated cells that maintain hallmarks of both stem and differentiated cells, and a loss of tissue barrier integrity. A signature feature of the mis-differentiated cells is the expression of the transcription factor Escargot (Esg), whose expression in healthy flies is typically limited to ISCs and their immediate daughters, enteroblasts (EBs). Esg is a member of the Snail family of transcription factors that are well-known for roles in development, as well as cancer initiation and metastasis, by regulating epithelial-mesenchymal transitions (EMT). Conserved targets of vertebrate Snail include cell-cell adhesion molecules, such as epithelial cadherin (E-Cadherin). Septate junctions (SJs), the Drosophila analog of vertebrate tight junctions (TJs), between absorptive enterocytes (ECs) and enteroendocrine (EE) cells regulate paracellular flux in the intestine and are required for the maintenance of normal intestinal homeostasis. Compromised SJs in the intestine correlate with increased permeability between the apical and basal epithelial surfaces of the intestine, as well as loss of intestinal barrier function. In Drosophila, Esg is required in ISCs fr maintenance and in EBs to mediate differentiation decisions: loss of esg results in a bias toward the secretory EE lineage. Interestingly, roughly half of the genes known to encode SJ components have been identified as putative direct repression targets of Esg, from a modified chromatic binding assay that detects Esg-binding regions in the genome and from transcriptome analyses of sorted ISC/EBs with varied esg expression. Therefore, the central hypothesis of this proposal is that mis- expression of esg in the intestine in response to damage or age alters the organization of intercellular junctions to disrupt intestinal tissue homeostasis. The proposed study examines this hypothesis through the following specific aims: SA 1) To determine the mechanisms by which esg expression changes in response to aging and stress. SA 2) To elucidate the relationship between Esg and septate junction proteins in the Drosophila intestine. These studies will contribute to the long-term objective in understanding how intestinal tissue homeostasis is maintained with regard to a key transcription program regulated by the Snail family transcription factor Esg and expand our knowledge in the mechanisms by the Snail family can influence tissue homeostasis, impact organ function, and drive tumorigenesis.