Mechanisms of Neurotensin in Intestinal Inflammation

描述（由申请人提供）：我们的结果表明，肽神经降压素（NT）及其高亲和力受体（NTR 1）通过激活促炎、增殖和抗凋亡基因的表达在结肠炎症和结肠癌的病理生理学中起关键作用。基因表达受microRNA负调控，导致mRNA降解和/或抑制翻译成蛋白质。miR也是炎症性肠病（IBD）的重要调节因子。我们最近报道，NT/NTR 1相互作用在人类结肠细胞差异调节microRNA的表达，影响结肠肿瘤的发生，通过刺激的miRNA反馈网络，涉及炎症和抗凋亡途径。这是文献中支持神经肽调节结肠上皮细胞中micorRNA表达的概念的第一个证据，并且这种相互作用在功能上与GI疾病的调节相关。在这里，我们将测试一个新的假设，即NTR 1调节的微小RNA miR-210和miR-133 a通过激活与炎症信号传导和NTR 1内化相关的途径在IBD样结肠炎的病理生理学中发挥重要作用。以下目标将解决这些假设。目的1将确定miR- 210在人结肠上皮细胞NT相关促炎反应中的重要性，并研究参与这种反应的上游和下游信号通路。目的2将评估miR-133 a在NTR 1运输中的重要性及其作为人结肠上皮细胞中促炎反应与受体运输的联系的作用，并研究引发这种反应的机制。使用人类疾病样本将证实目标1和2中发现的IBD相关性。目的3将确定NT和NTR 1与miRNA-210和133 a在结肠炎模型中的关系的功能意义。这方面的研究包括在结肠炎模型中使用NT和NTR 1缺陷小鼠，这将有助于验证NT相关的miR-210驱动的信号转导靶点和血管生成以及NT相关的miR-133 a相关受体转运。这些研究将促进我们对IBD发病机制的理解，并确定NTR 1- microRNA信号在这组疾病中的作用和机制。

DESCRIPTION (provided by applicant): Our results show that the peptide neurotensin (NT) and its high affinity receptor (NTR1) play a critical role in the pathophysiology of both colonic inflammation and colon cancer by activating expression of proinflammatory, proliferative and anti-apoptotic genes. Gene expression is negatively regulated by microRNAs, leading to mRNA degradation, and/or inhibition of translation into protein. MiRs are also important regulators of Inflammatory Bowel Disease (IBD). We recently reported that NT/NTR1 interactions in human colonocytes differentially regulate expression of microRNAs that affect colon tumorigenesis through stimulation of miRNA feedback networks involving inflammatory and anti-apoptotic pathways. This is the first evidence in the literature supporting the notion that neuropeptides modulate micorRNA expression in colonic epithelial cells and that this interaction is functionally correlated with modulation of a GI disease. Here we will test the novel hypothesis that the NTR1 - regulated microRNAs miR-210 and miR-133a play an important role in the pathophysiology of IBD-like colitis by activating pathways linked to inflammatory signaling and NTR1 internalization. The following aims will address these hypotheses. Aim 1 will determine the importance of miR- 210 in NT-associated proinflammatory responses in human colonic epithelial cells and examine the upstream and downstream signaling pathways involved in this response. Aim 2 will assess the importance of miR-133a in NTR1 trafficking and its role as a link of proinflammatory responses to receptor trafficking in human colonic epithelial cells and study the mechanisms eliciting this response. Use of human disease samples will confirm the IBD relevance of the findings in aims 1 and 2. Aim 3 will determine the functional significance of the relationship of NT and NTR1 to miRNAs-210 and 133a in models of colitis. Studies in this aim include use of NT, and NTR1 deficient mice in models of colitis that will help verify NT-associated miR-210-driven signaling targets and angiogenesis and NT-linked miR-133a-associated receptor trafficking. These studies should advance our understanding on the pathogenesis of IBD and define the role and mechanisms of NTR1- microRNA signaling in this group of diseases.