Regulation of Intestinal Epithelial Cell Proliferation

肠上皮细胞增殖的调节

• 批准号: 7898182
• 负责人: Vincent W Yang
• 金额: $ 7.93万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-20 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7898182
• 关键词: Apoptosis; Biological; Biological Process; Cancer cell line; Cell Cycle Arrest; Cell Line; Cell Proliferation; Cells; Citrobacter rodentium; Colon; Colorectal Cancer; Disease; Drosophila Kruppel protein; Enterocytes; Epithelial; Epithelial Cell Proliferation; Epithelial Cells; Epithelium; Erinaceidae; Exhibits; Family; Foundations; Functional disorder; Grant; Growth; HRAS gene; Homeostasis; Hyperplasia; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Intestines; Ligase; Link; Lipopolysaccharides; Longevity; Malignant Neoplasms; Mediating; Mediator of activation protein; Multipotent Stem Cells; Mus; Oncogenic; Organism; Paneth Cells; Pathway interactions; Physiological; Play; Post-Translational Protein Processing; Proliferating; Protein Family; Proteins; Rattus; Receptor Signaling; Regulation; Rodent; Role; STAT1 gene; STAT1 protein; Signal Pathway; Signal Transduction; Small Intestines; Stem cells; Stimulus; Surface; System; Testing; Therapeutic; Time; Tissues; Toll-like receptors; Transforming Growth Factor beta; Transforming Growth Factors; Transgenic Mice; Ubiquitin; Villus; Zinc Fingers; base; computerized data processing; developmental disease; enteric pathogen; in vivo Model; inhibitor/antagonist; insight; intestinal epithelium; notch protein; novel; numb protein; protein protein interaction; self-renewal; transcription factor

DESCRIPTION (provided by applicant): The mammalian intestinal epithelium is a tissue in which cell proliferation is closely linked to differentiation and programmed cell death. Recent studies have implicated several signaling pathways, including Wnt, Notch, Hedgehog, and TGF-beta family, as crucial regulators of intestinal epithelial homeostasis. However, the intracellular mediators for many of these pathways are not fully identified. The project supported by the grant on which this continuation application is based helped established the role played by two related Kruppel-like factors (KLFs), KLF4 and KLF5, in regulating intestinal epithelial proliferation and differentiation. KLF4 and 5 exhibit very different, at times opposite, biological activities. For example, KLF4 inhibits and KLF5 promotes cells proliferation, suggesting that KLF4 and KLF5 function to coordinate proliferation of intestinal epithelial cells. In the project period, we obtained exciting information about several novel aspects of the mechanism of action for the pro-proliferative KLF5 in mediating a number of physiologically relevant signaling processes. We showed that KLF5 is a crucial downstream mediator for the transforming effects of activated (oncogenic) H-Ras and K-Ras. We also obtained evidence that KLF5 is an important mediator for the pro-inflammatory response in intestinal epithelial cells elicited by Toll-like receptor (TLR) signaling, including bacterial lipopolysaccharide (LPS). Lastly, we identified a number of interacting proteins of KLF5 that might help explain its pro-proliferative and pro-inflammatory action. The central hypothesis of this proposal is that KLF5 is an essential mediator for the pro-proliferative and pro-inflammatory responses of intestinal epithelial cells to physiologic stimuli. We propose the following three specific aims in this continuation application: (1) To establish the function of KLF5 in mediating the oncogenic effect of activated K-Ras on intestinal epithelial cells, (2) To determine the role of KLF5 in mediating the pro-proliferative and pro-inflammatory responses to Toll-like receptor (TLR) signaling in intestinal epithelial cells, and (3) To investigate the role of a KLF5-interacting protein, protein inhibitor of activated STAT1 (PIAS1), in regulating KLFS's biological activities. Significance: The understanding of the mechanisms regulating proliferation and differentiation of the intestinal epithelium has the wide-range implication of gaining insights into the pathophysiology underlying many Gl diseases including cancer, infection, inflammatory bowel diseases, and a multitude of developmental disorders. The proposed project will characterize in detail the role of KLF5 in mediating signals that eventually result in the pro-proliferative or pro-inflammatory response of intestinal epithelial cells to various stimuli. A thorough delineation of KLF5's function in modulating these important biological processes may also help establish the foundation for potential therapeutic approaches for treating Gl diseases such as cancer and inflammatory bowel diseases.

描述(申请人提供)：哺乳动物的肠道上皮是一种细胞增殖与分化和程序性细胞死亡密切相关的组织。最近的研究表明，几个信号通路，包括Wnt、Notch、Hedgehog和转化生长因子-β家族，是肠上皮细胞动态平衡的重要调节因子。然而，这些通路中的许多细胞内介质还没有完全确定。这项继续申请所基于的赠款支持的项目帮助确定了两个相关的Kruppel样因子(KLF4和KLF5)在调节肠上皮细胞增殖和分化中所起的作用。KLF4和KLF5表现出非常不同的生物活性，有时甚至相反。例如，KLF4抑制细胞增殖，KLF5促进细胞增殖，提示KLF4和KLF5具有协调肠上皮细胞增殖的功能。在项目期间，我们获得了关于促增殖KLF5在调节一些生理相关信号过程中作用机制的几个新方面的令人兴奋的信息。我们发现KLF5是活化的(致癌)H-RAS和K-RAS转化效应的关键下游介体。我们还获得了证据表明，KLF5是Toll样受体(TLR)信号，包括细菌脂多糖(LPS)诱导的肠上皮细胞促炎反应的重要介质。最后，我们确定了KLF5的一些相互作用蛋白，可能有助于解释其促增殖和促炎作用。这一建议的中心假设是，KLF5是肠上皮细胞对生理刺激的促增殖和促炎反应的重要介质。在这一继续应用中，我们提出了以下三个特定的目的：(1)确定KLF5在介导激活的K-RAS对肠上皮细胞的致癌作用中的作用；(2)确定KLF5在介导肠上皮细胞对Toll样受体(TLR)信号的促增殖和促炎反应中的作用；(3)研究KLF5相互作用的蛋白，活化STAT1的蛋白抑制物(PIAS1)在调节KLFS生物学活性中的作用。意义：了解肠上皮细胞增殖和分化的调控机制具有广泛的意义，有助于深入了解许多G1疾病的病理生理学基础，包括癌症、感染、炎症性肠病和多种发育障碍。这项拟议的项目将详细描述KLF5在介导最终导致肠上皮细胞对各种刺激的促增殖或促炎反应的信号中的作用。深入了解KLF5的S在调节这些重要生物学过程中的功能，也可能有助于为治疗癌症和炎症性肠病等G1疾病的潜在治疗方法奠定基础。