Role of claudin 18 in regulation of lung stem/progenitor cell homeostasis

Claudin 18 在调节肺干/祖细胞稳态中的作用

基本信息

批准号：
9212851
负责人：
Zea Borok
金额：
$ 17.43万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
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：
2016-02-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9212851
关键词：
AGTR2 gene AMOT gene Actins Address Adherens Junction Adhesions Adult Alveolar Apical Apoptosis Cell Count Cell Differentiation process Cell Nucleus Cell Proliferation Cell membrane Cell physiology Cell-Matrix Junction Cells Complex Contact Inhibition Cytoskeleton Data Desmosomes Development Epithelial Equilibrium Exhibits Extracellular Domain F-Actin Family member G-Protein-Coupled Receptors Goals Growth Growth Factor Homeostasis In Vitro Inhibition of Cell Proliferation Injury Intercellular Junctions Ions Knock-out Knockout Mice LATS1 gene Lung Mass Spectrum Analysis Mechanics Mediating Molecular Natural regeneration Nuclear Nuclear Translocation Organ Organ Size Pathway interactions Permeability Phenotype Phosphorylation Phosphotransferases Population Process Proteins Regulation Role Series Signal Pathway Signal Transduction Site Stem cells Stimulus Stomach Tight Junctions Tissues Transcription Coactivator Transcriptional Coactivator with PDZ-Binding Motif Wild Type Mouse alpha catenin alveolar epithelium cell growth extracellular in vivo lung development lung injury lung regeneration lung repair novel organ regeneration prevent protein E protein protein interaction public health relevance repaired rho solute stem tissue regeneration transcription factor tumor tumorigenesis upstream kinase

项目摘要

DESCRIPTION (provided by applicant): Stem/progenitor cell proliferation and differentiation must be tightly regulated to maintain appropriate cell numbers for normal organ function while preventing tumorigenesis. Elucidation of mechanisms that regulate somatic stem/progenitor cell homeostasis is key to understanding how these populations are maintained and activated to meet demands for tissue regeneration following injury. Intercellular junctions, comprised of tight junctions (TJ), adherens junctions (AJ) and desmosomes, are sites of intercellular adhesion. Claudins are integral TJ proteins that regulate paracellular permeability. Claudin 18 (C18) is one of the most highly expressed Claudin family members in lung alveolar epithelium. We recently generated C18 knockout (KO) mice that exhibit increased lung epithelial permeability to ions and solutes. Intriguingly, C18 KO mice show expansion and increased proliferation of putative lung stem/progenitor cells (including alveolar epithelial type II (AT2) cells) and increased lung (and stomach) size, implicating integral TJ proteins (and C18 in particular) as novel regulators of epithelial stem/progenitor cell homeostasis and organ size. The Hippo signaling pathway regulates stem/progenitor cell function, organ size and regeneration through opposing effects on proliferation and apoptosis. Hippo signaling mediates contact inhibition of cell proliferation in vitro and limits tissue overgrowth in vivo via phosphorylation of upstream kinases that inhibit activity of orthologous downstream transcriptional co-activators, yes-associated protein (YAP) and transcriptional coactivator with PDZ binding motif (TAZ). Upstream regulators of Hippo signaling are not well characterized but include extracellular stimuli via G-protein coupled receptors, actin cytoskeleton, apical-basolateral polarity complexes and interactions with TJ-associated and AJ proteins. Integral TJ proteins (e.g., claudins) have not previously been shown to regulate Hippo signaling or YAP/TAZ activity. Preliminary studies demonstrate YAP/TAZ activation in C18 KO mice and association of YAP with C18 in wild type mice, leading us to hypothesize that C18 is a novel regulator of lung stem/progenitor cell homeostasis via modulation of YAP/TAZ subcellular localization/activity. The overall goal of this project is to investigate the role of C18 in regulating lung stem/progenitor cell homeostasis by addressing the following Specific Aims: 1) explore cellular mechanisms underlying lung phenotype of C18 KO mice: 2) investigate signaling mechanisms regulating stem/progenitor cell homeostasis in C18 KO mice; and, 3) characterize molecular mechanisms whereby C18 regulates YAP/TAZ signaling. Elucidation of mechanisms regulating lung stem/progenitor cell function and identification of novel pathways transducing growth-promoting signals from TJ to the nucleus have important implications for modulating stem/progenitor cell function and augmenting regeneration following lung injury.

描述（由适用提供）：必须严格调节茎/祖细胞的增殖和分化，以维持正常器官功能的适当细胞数，同时预防肿瘤发生。阐明调节体细胞/祖细胞体内稳态的机制是了解如何维持和激活这些种群以满足损伤后组织再生需求的关键。细胞间连接，由紧密连接（TJ），粘附连接（AJ）和脱染色体组成，是细胞间粘附的部位。 claudins是调节细胞细胞渗透性的整体TJ蛋白。 Claudin 18（C18）是肺肺泡上皮上皮中表达最高的Claudin家族成员之一。我们最近产生了C18敲除（KO）小鼠，该小鼠暴露了增加肺上皮渗透性对离子和固体。有趣的是，C18 KO小鼠表现出膨胀并增加了假定的肺茎/祖细胞（包括肺泡上皮II型（AT2）细胞），肺（和失速）的大小增加，隐含的积分TJ蛋白（尤其是C18）作为新型的调节剂上皮茎/祖细胞稳态和器官大小。河马信号通路通过对增殖和凋亡的相反影响来调节茎/祖细胞功能，器官大小和再生。河马信号传导通过磷酸化在体外介导了细胞增殖的接触抑制，并通过磷酸化在体内过度生长，从而抑制了直系同源的下游转录共激活剂的活性，YES相关蛋白（YAP）和与PDZ结合Motif（TAZ）的转录共激活者的活性。河马信号传导的上游调节剂没有很好地表征，但包括通过G蛋白偶联受体，肌动蛋白细胞骨架，顶质外侧极性复合物以及与TJ相关和AJ蛋白的相互作用的细胞外刺激。积分TJ蛋白（例如Claudins）以前尚未证明可以调节河马信号传导或YAP/TAZ活性。初步研究表明，C18 KO小鼠的YAP/TAZ激活以及YAP与C18在野生型小鼠中的关联，导致我们假设C18是通过调节YAP/TAZ亚细胞亚细胞定位/活性/TAZ的调节肺茎/祖细胞稳态的新调节剂。该项目的总体目标是通过解决以下特定目的来研究C18在调节肺茎/祖细胞稳态中的作用：1）探索C18 KO小鼠的肺肺表型的细胞机制：2）研究调节C18 KO小鼠中茎/祖细胞稳态的信号机制的信号机制。 3）表征了C18调节YAP/TAZ信号传导的分子机制。阐明了应对肺部干/祖细胞功能的机制，并鉴定从TJ到核转导促进生长信号的新途径对调节茎/祖细胞功能的调节和增强肺损伤后增长具有重要意义。