Regulation of Intestinal Epithelial Cell Proliferation

描述（由申请人提供）：哺乳动物肠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，Wnt、Notch、Hedgehog和TGF-β家族等信号通路是肠上皮细胞稳态的重要调节因子。然而，许多这些途径的细胞内介质没有完全确定。该继续申请所基于的赠款支持的项目帮助建立了两个相关的Kruppel样因子（KLF）KLF 4和KLF 5在调节肠上皮细胞增殖和分化中所起的作用。KLF 4和5表现出非常不同的，有时相反的生物活性。例如，KLF 4抑制细胞增殖而KLF 5促进细胞增殖，表明KLF 4和KLF 5的功能是协调肠上皮细胞的增殖。在项目期间，我们获得了关于促增殖KLF 5在介导许多生理相关信号传导过程中的作用机制的几个新方面的令人兴奋的信息。我们发现KLF 5是活化（致癌）H-Ras和K-Ras转化作用的关键下游介质。我们还获得的证据表明，KLF 5是一个重要的调解人的促炎反应在肠上皮细胞引起的Toll样受体（TLR）信号，包括细菌脂多糖（LPS）。最后，我们确定了一些KLF 5的相互作用蛋白，这可能有助于解释其促增殖和促炎症作用。该建议的中心假设是KLF 5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。我们在本延续申请中提出以下三个具体目标：（1）确定KLF 5在介导活化的K-Ras对肠上皮细胞的致癌作用中的功能。（2）确定KLF 5在介导肠上皮细胞对Toll样受体（TLR）信号的促增殖和促炎症反应中的作用，（3）研究KLF 5相互作用蛋白--活化的STAT 1蛋白抑制剂（PIAS 1）在KLFS生物学活性调节中的作用。重要性：对调节肠上皮细胞增殖和分化的机制的理解具有获得对许多GI疾病（包括癌症、感染、炎性肠病和多种发育障碍）的病理生理学的深入了解的广泛意义。拟议的项目将详细描述KLF 5在介导信号中的作用，这些信号最终导致肠上皮细胞对各种刺激的促增殖或促炎症反应。彻底描述KLF 5在调节这些重要生物过程中的功能也可以帮助建立用于治疗GI疾病如癌症和炎性肠病的潜在治疗方法的基础。

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.