Regulation of Cell Turnover During Epithelial Tissue Homeostasis

上皮组织稳态期间细胞更新的调节

• 批准号: 9911650
• 负责人: George Thomas Eisenhoffer
• 金额: $ 4.58万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9911650
• 关键词: Apoptosis; Apoptotic; Biological Models; Birth; Carcinoma; Cell Count; Cell Death; Cell Proliferation; Cell division; Cells; Cessation of life; Complement; Dangerousness; Data; Epithelial; Epithelial Cells; Epithelium; Event; Excision; Failure; Genetic; Goals; Graduate Education; Homeostasis; Human; Human Pathology; Hyperplasia; Image; Lead; Maintenance; Mediating; Molecular; Natural regeneration; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Phagocytes; Population; Regulation; Stem cells; Testing; Time; Tissues; Training and Education; WNT Signaling Pathway; Work; Zebrafish; gene function; insight; intestinal epithelium; overexpression; parent grant; response

Original R01GM124043 Project Summary Cells within epithelial tissues are continually being eliminated by apoptosis and replaced by cell proliferation, however the mechanisms that coordinate cell removal with cell division to retain constant cell numbers remain unknown. Failure to coordinate the birth and death of cells can lead to dysregulation of population numbers and compromised barrier function, or conversely, tissue hyperplasia and carcinoma formation. Thus, a thorough understanding of the genetic underpinnings guiding cellular turnover in epithelial tissues will provide insight into molecular pathways that can be leveraged against diverse human pathologies by enhancing the removal and replacement of defective cells. The goal of this proposal is to define the cell and molecular mechanisms that regulate cell turnover in epithelial tissues to maintain appropriate overall population numbers. My recent results suggest that clearance of excess or defective cells was a major influence in whether neighboring cells would divide, extrude or die. Importantly, this work also suggested that alterations in the ability to rapidly clear apoptotic cells from the epithelial tissues may lead to several epithelial pathologies, including decreased barrier function in the intestinal epithelium or the accumulation of dangerous cells to promote carcinoma formation. Yet, a model system has been lacking to study how changes in apoptotic cell clearance could impact cell turnover and tissue maintenance in living epithelia. To investigate cell turnover in a living epithelial tissue, we have developed a toolset to perturb gene function and perform live imaging of division and death in the epithelia of the developing zebrafish, providing unparalleled access to analyze cell turnover in real time. Using the developing zebrafish to study cellular turnover in an epithelial bilayer, we have uncovered that induction of damage in a subset of basal epithelial cells promotes live cell neighbors to act as phagocytes that rapidly clear the apoptotic cellular debris. The basal stem cells then undergo division to compensate for the cell loss and maintain tissue integrity and function. Our preliminary data suggests that inhibition of either cell death or WNT signaling eliminates the apoptosis-induced division and results in failed regeneration. Further, genetic overexpression of WNT signaling in the context of a damage response led to an increase in overall cell numbers. In the following proposal, we will test the hypothesis that clearance of WNT-containing apoptotic cells by neighboring stem cells directly influences their proliferation to drive cell turnover in epithelia. In Aim 1, we will determine how removal of dying cells stimulates stem cell-mediated replacement. In Aim 2, we will define the molecular mechanisms guiding apoptosis-induced proliferation to maintain overall cell numbers. In Aim 3, we will determine if apoptotic bodies and microparticles can promote stem cell proliferation. Together, these studies will help reveal the cell and molecular events regulating epithelial tissue homeostasis and how alterations lead to human pathogenic conditions.

原始R01GM124043项目摘要 上皮组织中的细胞不断被凋亡消除，并被细胞增殖所取代， 然而 未知。无法协调细胞的出生和死亡会导致人口数量失调，并且 障碍功能损害，或反之，组织增生和形成癌。因此，一个彻底的 了解上皮组织中指导细胞周转的遗传基础的理解将为您提供洞察力 通过增强去除和 替代有缺陷的细胞。该建议的目的是定义细胞和分子机制 调节上皮组织中的细胞转换以保持适当的总体人群数量。我的 最近的结果表明，清除过量或有缺陷的细胞是对邻近的主要影响 细胞会分裂，挤出或死亡。重要的是，这项工作还表明，快速的能力改变了 来自上皮组织的清晰凋亡细胞可能导致几种上皮病理，包括降低 肠上皮或危险细胞积累以促进癌的障碍功能 形成。但是，模型系统缺乏研究凋亡细胞清除的变化如何影响 活细胞和组织维持的上皮细胞。为了研究活细胞组织中的细胞转换， 我们已经开发了一种工具集来扰动基因功能并执行分裂和死亡的实时成像 发展中的斑马鱼的上皮，可实时实时分析细胞转换。使用 发育中的斑马鱼研究上皮双层中的细胞更新，我们发现了诱导 基础上皮细胞子集中的损害促进活细胞邻居充当吞噬细胞，迅速清除 凋亡细胞碎片。然后，基底干细胞进行分裂以补偿细胞损失，并 保持组织完整性和功能。我们的初步数据表明抑制细胞死亡或Wnt 信号传导消除了凋亡引起的分裂，并导致再生失败。此外，遗传 在损伤响应的背景下，Wnt信号的过表达导致整体细胞数量增加。 在以下提案中，我们将测试以下假设 通过相邻的干细胞直接影响它们的增殖，以驱动上皮细胞的流动。目标 1，我们将确定垂死细胞的去除如何刺激干细胞介导的替代。在AIM 2中，我们将 定义指导凋亡引起的增殖以维持总体细胞数量的分子机制。在 AIM 3，我们将确定凋亡的身体和微粒是否可以促进干细胞增殖。一起， 这些研究将有助于揭示调节上皮组织稳态的细胞和分子事件，以及如何 改变导致人类的致病条件。