Intestinal Mucosal Growth in Health and Surgical Diseases

摘要 肠粘膜生长的抑制通常发生在各种严重的外科疾病中，特别是 在接受大规模胃肠道手术切除，然后用全 肠外营养（TPN）。破坏的粘膜更新损害肠道屏障功能障碍并导致败血症 在某些情况下，还会导致多器官功能障碍综合征和死亡。有效的治疗方法， 患有严重外科疾病的患者的肠上皮完整性是有限的， 在应激环境中调节肠粘膜更新的机制还知之甚少。在持续的支持下 在这个项目中，我们的小组是第一个涉及RNA结合蛋白（RBP）和长非编码RNA的小组 173在肠道粘膜生长中的作用，并显示RBP HuR和lncRNA uc.173的失调损害了 上皮更新，损害上皮宿主防御，并破坏肠屏障。但 HuR和uc.173的失调如何影响肠粘膜的生长以及它们如何影响肠粘膜的生长仍然是未知的。 研究结果可用于治疗外科重症患者。快速自我更新 肠粘膜由位于隐窝基底的肠干细胞（ISCs）驱动。潘氏细胞 构成小肠中ISC的生态位，并提供多种分泌（WNT，EGF）和表面- 结合的（Notch配体）小生境信号对于ISC的维持和功能至关重要。线粒体内稳态 是维持PC/ISC生态位所必需的，而线粒体功能的破坏导致PC缺陷 回肠炎我们的初步研究表明，靶向HuR缺失或uc.173诱导的PC缺陷。 沉默导致在体内以及离体ISC活性的伴随损失， 抑制uc.173也导致线粒体功能障碍，沿着WNT 3和Notch水平降低 PC中的配体。基于这些令人兴奋的观察，我们现在提出范式转移假说 HuR和uc.173通过维持线粒体内稳态调节PC/ISC生态位， 在外科危重疾病中调节肠粘膜更新和适应。两个具体目标是 提出了检验假设：1）确定PC/ISC生态位在HuR/uc.173调节的细胞中的确切作用。 关键手术条件下的肠粘膜生长;和2）确定HuR和uc.173是否调节 PC/ISC生态位功能通过调节线粒体代谢来响应关键的手术应激。 这些特定目标的完成将揭示肠道肿瘤发病机制的新机制。 严重外科疾病患者的粘膜生长抑制。它还将建立一个基本的 为开发新的有效治疗剂以通过靶向肠粘膜生长/适应提供了基础。 通过HuR和uc.173的PC/ISC生态位活性。

Abstract Inhibition of intestinal mucosal growth occurs commonly in various critical surgical disorders, particularly in patients who undergo massive gastrointestinal surgical resections and are then supported with total parenteral nutrition (TPN). Disrupted mucosal renewal impairs gut barrier dysfunction and leads to sepsis and, in some instances, multiple organ dysfunction syndrome and death. Effective therapies to preserve the intestinal epithelial integrity in patients with critical surgical illnesses are limited, as the mechanisms that regulate gut mucosal renewal in stressful environments are poorly understood. With on-going support for this project, our group was the first to implicate RNA-binding proteins (RBPs) and long noncoding RNAs (lncRNAs) in gut mucosal growth and to show that dysregulation of RBP HuR and lncRNA uc.173 impairs epithelial renewal, compromises epithelial host defenses, and disrupts the intestinal barrier. However, it remains unknown how dysregulated HuR and uc.173 affect growth of the intestinal mucosa and how these findings can be exploited to benefit patients with critical surgical illnesses. Rapid self-renewal of the intestinal mucosa is driven by intestinal stem cells (ISCs) located at the crypt base. Paneth cells (PCs) constitute the niche for ISCs in the small intestine and provide multiple secreted (WNT, EGF) and surfaced- bound (Notch ligand) niche signals essential for ISC maintenance and function. Mitochondrial homeostasis is essential for sustaining the PC/ISC niche, whereas disrupted mitochondrial function leads to PC defects and ileitis. Our preliminary studies indicate that defects in PCs induced by targeted HuR deletion or uc.173 silencing resulted in the concomitant loss of ISC activity in vivo as well as ex vivo and that HuR knockout and uc.173 inhibition also caused mitochondrial dysfunction, along with reduced levels of WNT3 and Notch ligands in PCs. Building on these exciting observations, we now propose the paradigm-shifting hypothesis that HuR and uc.173 regulate the PC/ISC niche by maintaining mitochondrial homeostasis, in turn regulating intestinal mucosal renewal and adaptation in critical surgical diseases. Two specific aims are proposed to test the hypothesis: 1) to define the exact role of the PC/ISC niche in HuR/uc.173-regulated intestinal mucosal growth under critical surgical conditions; and 2) to determine if HuR and uc.173 regulate PC/ISC niche function by modulating mitochondrial metabolism in response to critical surgical stress. Completion of these specific aims will uncover novel mechanisms underlying the pathogenesis of intestinal mucosal growth inhibition in patients with critical surgical disorders. It will also establish a fundamental basis for developing new effective therapeutics to promote gut mucosal growth/adaptation by targeting the PC/ISC niche activity via HuR and uc.173.