Role of Intestinal Cell Kinase in the Intestinal Epithelium

肠细胞激酶在肠上皮中的作用

• 批准号: 8316337
• 负责人: Zheng Fu
• 金额: $ 15.04万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8316337
• 关键词: Ablation; Address; Adult; Architecture; Biological; Biological Process; Cell Cycle; Cell Cycle Progression; Cell Death; Cell Differentiation process; Cell Line; Cell Survival; Cells; Complex; Data; Defect; Development; Diagnosis; Epithelial; Epithelial Cell Proliferation; Epithelial Cells; Epithelium; Equilibrium; Gastrointestinal Diseases; Goals; Growth; Homeostasis; In Vitro; Injury; Intestinal Neoplasms; Intestines; Knock-in Mouse; Knockout Mice; Large Intestine Carcinoma; Lead; Life; Maintenance; Malignant neoplasm of gastrointestinal tract; Mediating; Messenger RNA; Molecular; Morphogenesis; Natural regeneration; Outcome; Outcome Study; Pathway interactions; Phosphorylation; Phosphotransferases; Physiological; Physiology; Play; Prevention; Protein Kinase; Protein-Serine-Threonine Kinases; Proteins; Radiation Injuries; Raptors; Regulation; Role; Signal Pathway; Signal Transduction; Site; Small Intestines; Staging; Stem cells; Structure; Testing; Tissues; Translations; Undifferentiated; Work; base; cell fate specification; gastrointestinal; gastrointestinal epithelium; in vivo; in vivo regeneration; intestinal epithelium; mTOR protein; mouse model; notch protein; novel; progenitor; programs; public health relevance; repaired; response; restoration; self-renewal; small hairpin RNA; stem; stem cell fate; stem cell population; therapeutic target

DESCRIPTION (provided by applicant): A delicate balance of cell renewal, differentiation and cell death within the intestinal epithelium is crucial to maintain the gastrointestinal tissue structure and function which form the basis for normal physiology of the gut. Intestinal epithelium undergoes a programmed self-renewal throughout adult life and a rapid regeneration after injury due to the presence of multipotent epithelial stem and progenitor cells. Various signaling pathways have been implicated to play a role in the control of stem cell activity, proliferation, lineage commitment, terminal differentiation and cell survival during normal development and homeostasis of the gastrointestinal epithelium. Deregulation of these signaling pathways can lead to intestinal neoplasia. In this proposal, we focus on the elucidation of a novel protein kinase signaling pathway that may play an important role in regulating the development and regeneration of the intestinal epithelium. Intestinal cell kinase (ICK) is a highly conserved serine/threonine protein kinase. In the small intestine, the ICK mRNA localizes specifically to the undifferentiated intestinal epithelium in the lower crypt compartment where stem cells reside suggesting that ICK may play a role in epithelial replication, lineage specification and cell fate determination in crypt epithelium. Our preliminary data shows [sic] that ICK expression in crypt epithelium is significantly induced during crypt epithelium regeneration when stem/progenitor cells actively replicate. Our in vitro knockdown studies in intestinal epithelial cell lines suggest that ICK promotes intestinal epithelial proliferation and G1 cell cycle progression, possibly by selectively regulating protein translation of key cell cycle regulators through the mammalian target of rapamycin (mTOR) pathway. Taken together these data support our current working hypothesis that ICK mediated signaling regulates proliferation and differentiation of epithelial stem cells and their progenitors in the intestinal epithelium during normal intestinal ontogeny and/or during the crypt epithelium regeneration in response to mucosal injury. To test this hypothesis, we propose three specific aims. Aim 1: Determine whether ICK mediated signaling regulates epithelial proliferation and differentiation in vivo during normal development and homeostatic maintenance of the intestinal epithelium; Aim 2: Determine whether ICK mediated signaling is important for intestinal epithelial repair and regeneration in response to mucosal injury; Aim 3: Determine whether ICK mediated signaling regulates intestinal epithelial cell proliferation and differentiation by modulating protein translation of cell cycle regulators through the mTOR signaling pathway. PUBLIC HEALTH RELEVANCE: The study of the ICK signaling pathway will provide a better understanding of the molecular basis for the regulation of stem cell fate and function during intestinal epithelium development and regeneration. Thus, the outcomes from this study will help to set up the stage for examining the role of ICK as a potential therapeutic target for diagnosis, prevention and treatment of gastrointestinal diseases and cancer.

描述（由申请人提供）：肠上皮内细胞更新、分化和细胞死亡的微妙平衡对于维持胃肠组织结构和功能至关重要，胃肠组织结构和功能构成肠道正常生理学的基础。由于多能上皮干细胞和祖细胞的存在，肠上皮在整个成年过程中经历程序性自我更新，并在损伤后快速再生。在胃肠道上皮的正常发育和稳态过程中，各种信号通路在干细胞活性、增殖、谱系定型、终末分化和细胞存活的控制中发挥作用。这些信号通路的失调可能导致肠道肿瘤。在本提案中，我们重点阐明一种新型蛋白激酶信号通路，该通路可能在调节肠上皮的发育和再生中发挥重要作用。 肠细胞激酶（ICK）是一种高度保守的丝氨酸/苏氨酸蛋白激酶。在小肠中，ICK mRNA 特异性定位于干细胞所在的隐窝下部未分化的肠上皮，这表明 ICK 可能在隐窝上皮的上皮复制、谱系规范和细胞命运决定中发挥作用。我们的初步数据表明，当干细胞/祖细胞活跃复制时，隐窝上皮再生期间，隐窝上皮中的 ICK 表达被显着诱导。我们对肠上皮细胞系的体外敲低研究表明，ICK 可能通过哺乳动物雷帕霉素靶点 (mTOR) 途径选择性调节关键细胞周期调节因子的蛋白翻译，从而促进肠上皮增殖和 G1 细胞周期进程。综上所述，这些数据支持我们目前的工作假设，即在正常肠个体发育期间和/或响应粘膜损伤的隐窝上皮再生期间，ICK介导的信号调节肠上皮中上皮干细胞及其祖细胞的增殖和分化。 为了检验这一假设，我们提出了三个具体目标。目标1：确定ICK介导的信号传导是否在肠上皮正常发育和稳态维持过程中调节体内上皮增殖和分化；目标 2：确定 ICK 介导的信号传导对于响应粘膜损伤的肠上皮修复和再生是否重要；目标 3：确定 ICK 介导的信号传导是否通过 mTOR 信号通路调节细胞周期调节因子的蛋白翻译来调节肠上皮细胞增殖和分化。 公众健康相关性：ICK信号通路的研究将有助于更好地理解肠上皮发育和再生过程中干细胞命运和功能调节的分子基础。因此，这项研究的结果将有助于为检查 ICK 作为诊断、预防和治疗胃肠道疾病和癌症的潜在治疗靶点的作用奠定基础。