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（由申请人提供）：所有生物体的一个显着特征是它们能够适应周围环境的变化，并且在成年果蝇的肠道中观察到类似程度的可塑性。肠干细胞 (ISC) 增殖和分化以维持构成器官的吸收细胞和分泌细胞群，然而，增殖和分化之间的平衡会因损伤、炎症或其他外部损伤而被打破。衰老，导致干细胞不受控制的增殖，维持干细胞和分化细胞特征的错误分化细胞的积累，以及组织屏障完整性的丧失。 错误分化细胞的标志性特征是转录因子 Escargot (Esg) 的表达，其在健康果蝇中的表达通常仅限于 ISC 及其直系子细胞，肠成细胞 (EBs) 是 Snail 转录家族的成员。脊椎动物 Snail 的保守靶点包括细胞间转化，从而在发育以及癌症发生和转移中发挥重要作用。吸收性肠上皮细胞 (EC) 和肠内分泌 (EE) 细胞之间的粘附分子，例如上皮钙粘蛋白 (E-钙粘蛋白) (SJ)，果蝇类似的脊椎动物紧密连接 (TJ)，可调节肠道内的细胞旁通量。维持正常肠道稳态所需的肠道 SJ 受损与肠道之间的通透性增加相关。肠的顶端和基底上皮表面，以及肠屏障功能的丧失，在果蝇中，ESG 是 ISC 的维持和 EB 介导分化决策所必需的：ESG 的丧失会导致分泌型 EE 谱系的偏向。通过检测基因组中 Esg 结合区域的改良染色结合测定，大约一半已知编码 SJ 成分的基因已被确定为推定的 Esg 直接抑制目标对具有不同 esg 表达的分类 ISC/EB 进行转录组分析 因此，该提案的中心假设是肠道中因损伤或年龄而发生的 esg 错误表达会改变细胞间连接的组织，从而破坏肠道组织稳态。该假设通过以下具体目标： SA 1) 确定 ESG 表达随衰老和压力而变化的机制 SA 2) 阐明 Esg 与隔膜连接之间的关系。这些研究将有助于了解 Snail 家族转录因子 Esg 调节的关键转录程序如何维持肠道组织稳态，并扩展我们对 Snail 家族机制的了解。可以影响组织稳态、影响器官功能并驱动肿瘤发生。