Neutrophil interactions with intestinal epithelial cells

描述(由申请人提供)：对通知编号(NOT-OD-09-058)的响应，通知标题：NIH宣布可为竞争性修订申请提供恢复资金。人类炎症性肠病(IBD)的病因包括异常的白细胞反应和上皮屏障功能障碍。连接黏附分子(JAM)家族蛋白被证明同时调节上皮紧密连接功能和白细胞迁移。我们的结果表明，JAM蛋白在肠黏膜炎症的病理生理学中起着重要作用，例如在IBD中观察到的情况。Jam-A是迄今为止最具特征的家族成员，但对Jam-A功能的体内研究一直有限，结果往往相互矛盾。一个困难是确定JAM-A在多种细胞类型上的作用，这些细胞类型可能有助于观察到的表型。利用骨髓嵌合体和相关疾病模型以及互补的体外系统进行的重点实验将提供剖析上皮细胞和白细胞JAM-A对粘膜通透性和肠道炎症的重要贡献的手段。我们的初步结果表明，JAM-A在调节中性粒细胞在肠道中的招募方面发挥了重要作用，详细的研究结果与代偿性B细胞增殖一致，这可能保护这些动物在结肠通透性大幅增加的情况下免受自发性结肠炎的影响。这些观察结果表明，JAM-A通过直接调节白细胞功能和通过间接调节结肠上皮的通透性，在肠道内稳态中发挥核心作用。扩展这些发现的进一步研究显然是有必要的，并可能显著增强我们对果酱和粘膜动态平衡之间的关系的理解，以及更广泛地说，对粘膜免疫功能的基本调节。 公共卫生相关性：人类炎症性肠病(IBD)的特点是白细胞反应异常和肠道屏障功能障碍。因此，研究连接黏附分子-A(JAM-A)对粘膜通透性和肠道炎症的作用，对于了解IBD的病理生理机制和开发减轻肠道炎症的治疗靶点具有重要意义。

DESCRIPTION (provided by applicant): Response to Notice Number (NOT-OD-09-058), Notice Title: NIH Announces the Availability of Recovery Funds for Competitive Revision Applications. The etiology of human inflammatory bowel disease (IBD) includes both aberrant leukocyte responses and epithelial barrier dysfunction. Junctional Adhesion Molecule (JAM) family of proteins have been shown to regulate both epithelial tight junction function and leukocyte transmigration. Our results suggest that JAM proteins play an important role in the pathophysiology of intestinal mucosal inflammation such as observed in IBD. JAM-A is the best characterized family member to date, but in-vivo studies of JAM-A function have been limited and the results often contradictory. One difficulty has been determining the role of JAM-A on multiple cell types potentially contributing to observed phenotypes. Focused experiments employing bone marrow chimeras and relevant disease models alongside complementary in vitro systems will provide the means to dissect the important contributions of epithelial and leukocyte JAM-A to mucosal permeability and intestinal inflammation. Our preliminary results suggest an important role for JAM-A in regulation of PMN recruitment in the intestine and detail findings consistent with compensatory B-cell hyperplasia that may protect these animals from developing spontaneous colitis in face of a large increase in colonic permeability. These observations suggest that JAM-A plays a central role in intestinal homeostasis by direct regulation of leukocyte function and by indirect means through regulation of permeability of the colonic epithelium. Further research extending these findings is clearly warranted and may significantly enhance our understanding of the relationship between JAMs and mucosal homeostasis and, more broadly, basic regulation of mucosal immune function. PUBLIC HEALTH RELEVANCE: Human inflammatory bowel disease (IBD) is characterized by both aberrant leukocyte responses and intestinal barrier dysfunction. Research focused on the contributions of junctional adhesion molecule-A (JAM-A) to mucosal permeability and intestinal inflammation should, therefore, be highly relevant in understanding pathophysiology of IBD and in the development of therapeutic targets to ameliorate intestinal inflammation.