The role of the mu-Opioid Receptor in Inflammatory Bowel Disease Pathology and Th

描述(申请人提供)：炎症性肠病(IBD)在北美影响着130多万人，并与显著的发病率和死亡率有关。IBD的病因尚不清楚，有必要进行慢性药物治疗。该提案的长期目标是验证靶向5-阿片受体(MOR)的药物作为治疗IBD的潜在疗法，并确定其作用机制。初步数据显示，MOR激动剂可改善DSS结肠炎。然而，DSS介导的保护作用机制仍不清楚。初步研究还表明，MOR可在体内诱导IL-22mRNA的表达。IL-22是STAT3磷酸化的有效诱导剂，其他初步数据表明，MOR激动剂可诱导培养的肠细胞中STAT3的激活。因此，我们假设MOR信号的激活在DSS诱导的结肠炎中起着有益的作用，这是通过上调肠细胞中的STAT3信号来实现的。由于IEC和单核免疫细胞都对MOR激动剂有反应，而树突状细胞(DC)产生STAT3激活细胞因子IL-22，我们将使用组织特异性的MOR消融来解剖MOR保护信号对抗结肠损伤所必需的细胞室(S)。这一建议的具体目的是：1)确定IL-22/STAT3信号在MOR介导的细胞保护功能中的作用；2)确定负责MOR介导的保护功能的细胞隔室(S)。MOR介导的信号对IBD的影响和分子机制将通过应用于野生型和组织特异性基因缺陷小鼠的急性肠道损伤(DSS结肠炎和缺血/再灌注损伤)实验模型来确定。这项工作将得到一系列分子和细胞生物学研究以及分子药理学实验的补充。 公共卫生相关性：与公共健康相关：随着时间的推移，IBD患者往往对他们的治疗变得无反应，使手术成为他们唯一的手段。因此，患者迫切需要新的更好的治疗方法，以维持缓解并避免手术的相关风险和发病率。这项工作有可能通过激活Mu阿片受体信号而提出新的治疗方式。

DESCRIPTION (provided by applicant): Inflammatory Bowel Diseases (IBD) affect over 1.3 million people in North America, and are associated with significant morbidity and mortality. The causes of IBD remain unknown, and chronic medicinal therapy is necessary to manage them. The long term objectives of the proposal are to validate drugs that target the 5- opioid receptor (MOR) as potential therapeutics for IBD, and to determine their mechanisms of action. Preliminary data shows that MOR agonist ameliorates DSS colitis. However, the mechanism of action of DSS- mediated protection remains unknown. Prelminary studies also show MOR-induced IL-22 mRNA expression in vivo. IL-22 is a potent inducer of STAT3 phosphorylation, and other prelminary data shows the MOR agonist induces STAT3 activation in cultured enterocytes. Consequently, we hypothesize that the activation of MOR signaling plays a beneficial role in DSS-induced colitis through an up-regulation of STAT3 signaling in enterocytes. Because both IECs and mononuclear immune cells respond to MOR agonist, and dendritic cells (DCs) produce the STAT3 activating cytokine IL-22, we will use tissue-specific ablation of MOR to dissect the cell compartment(s) necessary for MOR-protective signaling against colonic injury. The specific aims of this proposal are to: 1) identify the role of IL-22/STAT3 signaling in MOR-mediated cyto-protective function; and 2), identify the cell compartment(s) responsible for the MOR-mediated protective function. The impact and molecular mechanisms of MOR-mediated signaling on IBD will be determined using acute experimental models of intestinal injury (DSS-colitis and ischemia/reperfusion injury) applied to wild-type and tissue-specific, gene-deficient mice. This work will be complemented with a series of molecular and cellular biology studies as well as molecular pharmacology experiments. PUBLIC HEALTH RELEVANCE: Relevance to public health: IBD patients often become non-responsive to their therapies over time, leaving surgery as their only recourse. Consequently, new and better therapies are desperately needed for patients, to both maintain remission and to stave off the associated risks and morbidity of surgery. This work has the potential to bring forward new therapeutic modalities through activation of mu opioid receptor signaling.