Molecular mechanisms regulating intestinal stem cell activities and homeostasis

调节肠道干细胞活性和稳态的分子机制

基本信息

批准号：
9269101
负责人：
XINHUA LIN
金额：
$ 30.81万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9269101
关键词：
Address Adult Basement membrane Biological Models Cell Differentiation process Cell Proliferation Cells Cellular biology ChIP-seq Data Digestive System Disorders Disease Drosophila genus Dystroglycan Endocytosis Enterochromaffin Cells Enterocytes Enteroendocrine Cell Epidermal Growth Factor Receptor Epithelium Extracellular Matrix GAG Gene Gene Targeting Genetic Goals Grant Homeostasis Human Intestines Laboratories Life Light Maintenance Malignant Neoplasms Mediating Methods Midgut Molecular Molecular Biology Organ Outcome Pathway interactions Physiological Play Property Publishing RNA Interference Regulation Role Signal Pathway Signal Transduction Stem cells Structure System Tissue Differentiation Tissue Model Undifferentiated adult stem cell daughter cell experimental study gastrointestinal epithelium human disease insight intestinal epithelium perlecan public health relevance receptor response self-renewal smoothened signaling pathway stem cell fate stem cell niche

项目摘要

DESCRIPTION (provided by applicant): The normal structure and function of adult organs is maintained by resident stem cells and their progeny throughout life. The proliferation of adult stem cells and differentiation of their progeny must be tightly controlled. One of the best examples is the adult gastrointestinal epithelium which is constantly being renewed with the progeny of ISCs. ISCs replenish the intestinal epithelium every few days and represent a general model for tissue differentiation and stem cell properties. Deregulation of the regulatory mechanisms could result in the depletion of stem cells or in the excessive proliferation of stem cells/progenitor cells, eventually leading to diseases such as cancer. The long-term goal of this proposal is to elucidate the molecular mechanism(s) by which adult ISC activities and homeostasis are regulated. We will use Drosophila adult midgut as a system. Over the past 7 years, studies in this system have demonstrated that the JAK/Stat, Dpp (Drosophila BMP), EGFR, and Hippo signaling pathways are required for midgut homeostasis under normal physiological conditions or in response to environmental challenges. However, currently it is unknown how these signaling pathways execute their signaling activities through their downstream target genes to control gut homeostasis. In our recent studies, we have demonstrated that BMP pathway, Hh signaling pathway, and HSPGs can regulate stem cell proliferation, differentiation, and stem cell-niche interactions in different manners, and play essential roles in regulating stem cell fate and homeostasis. Moreover, we have conducted ChIP- Seq experiments combined with RNAi-mediated screens to identify JAK/STAT downstream target genes. On the basis of our recent published studies and our unpublished data, we have proposed a number of important hypotheses aimed at elucidation of the molecular mechanisms regulating ISC activities and homeostasis. In this proposal, we will use Drosophila adult midgut as a system to address three independent, but highly related issues in the maintenance of gut homeostasis. First, we will examine mechanism(s) of the JAK/STAT signaling pathway in regulating gut homeostasis. Second, we will define the mechanism(s) of Dpp signaling in regulating stem cell activity by mediating tracheal-gut interactions. Third, we will examine the mechanisms of Perlecan/ECM in the regulation of ISC-niche interactions. Taken together, integration of these three important regulatory mechanisms will enhance our understanding of the maintenance of homeostasis, signaling transduction, and stem cell regulation. The outcomes of this will shed light on human diseases associated with deregulation of ISC activities and gut homeostasis.

描述（由申请人提供）：成体器官的正常结构和功能是由常驻干细胞及其后代维持的。成体干细胞的增殖及其后代的分化必须受到严格控制。成体胃肠道上皮随着 ISC 的后代不断更新，每隔几天就会补充肠上皮，并代表组织分化和干细胞特性失调的一般模型。机制可能导致干细胞耗竭或干细胞/祖细胞过度增殖，最终导致癌症等疾病。该提案的长期目标是阐明成人 ISC 的分子机制。我们将使用果蝇成体中肠作为一个系统。在过去的 7 年里，对该系统的研究表明，JAK/Stat、Dpp（果蝇 BMP）、 EGFR 和 Hippo 信号通路是正常生理条件下或应对环境挑战时中肠稳态所必需的，然而，在我们最近的研究中，目前尚不清楚这些信号通路如何通过其下游靶基因执行其信号活动。我们证明BMP通路、Hh信号通路和HSPGs可以以不同的方式调节干细胞增殖、分化和干细胞生态位相互作用，并在调节干细胞命运和稳态中发挥重要作用。将 ChIP-Seq 实验与 RNAi 介导的筛选相结合，以鉴定 JAK/STAT 下游靶基因。根据我们最近发表的研究和未发表的数据，我们提出了许多重要的假设，旨在阐明调节的分子机制。 ISC 活动和稳态在本提案中，我们将使用果蝇成体中肠作为一个系统来解决维持肠道稳态的三个独立但高度相关的问题。 JAK/STAT 信号通路在调节肠道稳态中的作用其次，我们将定义 Dpp 信号通过介导气管-肠道相互作用来调节干细胞活性的机制。总而言之，这三种重要调节机制的整合将增强我们对维持稳态、信号转导和干细胞调节的理解，其结果将揭示与失调相关的人类疾病。 ISC 活动和肠道稳态。