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

• 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
• 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

 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.

 描述（由适用提供）：所有生物体的显着特征是它们适应周围环境变化的能力，并且在细胞和组织的水平上观察到相似程度的可塑性。在成年果蝇的肠道中，肠道干细胞（ISC）增殖并分化以维持构成器官的吸收和秘书细胞的种群。然而，增殖和分化之间的平衡是由诸如损伤，感染或衰老等外部侮辱倾斜的，导致干细胞的不受控制，这是差异分化的细胞的积累，这些细胞的积累维持了干细胞和分化细胞的标志，以及组织屏障完整性的丧失。一个 差异化细胞的签名特征是转录因子escargot（ESG）的表达，其在健康苍蝇中的表达通常仅限于ISC及其直接女儿，肠细胞（EBS）。 ESG是通过调节上皮 - 间质转变（EMT）而在发育以及癌症倡议和转移中众所周知的转录因子家族的成员。脊椎动物蜗牛的保守靶标包括细胞细胞粘附分子，例如上皮钙粘蛋白（E-钙粘着蛋白）。分隔连接（SJS），脊椎动物紧密连接连接（TJ）的果蝇类似物，吸收性肠上细胞（ECS）和肠内分泌（EE）细胞之间调节肠道副细胞通量，并且是维持正常肠道稳态所必需的。肠中的SJS受损与肠的顶端和基本上皮表面之间的渗透性以及肠屏障功能的丧失相关。在果蝇中，在ISCS FR维护和EBS到媒体分化决策中需要ESG：ESG的丢失导致对秘密EE谱系的偏见。有趣的是，已经大约一半已知编码SJ成分的基因已被确定为ESG的推定直接表达靶标，这是从检测基因组中的ESG结合区域的改进的色度结合测定中，并从分类的ISC/EB的转录组分析中，具有不同的ESG表达。因此，该提议的核心假设是，肠道中ESG的误解是响应损害或年龄的响应，改变了细胞间连接的组织以破坏肠道组织稳态。拟议的研究通过以下特定目的检查了这一假设：SA 1）确定ESG表达在衰老和压力中发生变化的机制。 SA 2）阐明果蝇肠中ESG和分离株连接蛋白之间的关系。这些研究将有助于长期目标，以了解如何维持由蜗牛家族转录因子ESG调节的关键转录程序，并扩大蜗牛家族在机制上的知识会影响组织体内稳态，影响器官功能和驱动肿瘤发生的机制。