Molecular mechanisms regulating intestinal stem cell activities and homeostasis

 描述（由申请人提供）：成体器官的正常结构和功能由常驻干细胞及其后代维持。成体干细胞的增殖及其后代的分化必须严格控制。最好的例子之一是成体胃肠上皮，其不断被ISC的后代更新。ISCs每隔几天补充肠上皮细胞，代表组织分化和干细胞特性的一般模型。调节机制的失调可能导致干细胞的耗竭或干细胞/祖细胞的过度增殖，最终导致疾病，如癌症。这项建议的长期目标是阐明成人ISC活动和稳态调节的分子机制。我们将使用果蝇成虫中肠作为一个系统。在过去的7年中，该系统的研究已经证明，JAK/Stat，Dpp（果蝇BMP），EGFR和Hippo信号通路是正常生理条件下或响应环境挑战时中肠稳态所必需的。然而，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传导活动以控制肠道内稳态。在我们最近的研究中，我们已经证明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，并且在调节干细胞命运和稳态中起重要作用。此外，我们进行了ChIP-Seq实验结合RNAi介导的筛选以鉴定JAK/STAT下游靶基因。在我们最近发表的研究和未发表的数据的基础上，我们提出了一些重要的假设，旨在阐明调控ISC活动和稳态的分子机制。在这个建议中，我们将使用果蝇成年中肠作为一个系统，以解决三个独立的，但高度相关的问题，在维持肠道内稳态。首先，我们将研究JAK/STAT信号通路在调节肠道稳态中的机制。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。第三，我们将研究串珠素/ECM在调节ISC-生态位相互作用中的机制。总之，这三个重要的调节机制的整合将提高我们的理解，维持稳态，信号转导和干细胞调节。这一结果将揭示与ISC活动和肠道稳态失调相关的人类疾病。

 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.