Neutrophil interactions with intestinal epithelial cells

中性粒细胞与肠上皮细胞的相互作用

• 批准号: 7847792
• 负责人: CHARLES A PARKOS
• 金额: $ 31万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7847792
• 关键词: Acute; Adoptive Transfer; Animals; B-Lymphocytes; Biological Assay; Bone Marrow; Bone Marrow Cells; Cells; Chimera organism; Colitis; Colon; Complement; Defect; Development; Disease; Disease model; Epithelial; Epithelial Cells; Epithelium; Etiology; Excision; Face; Family member; Functional disorder; Funding; Generations; Homeostasis; Human; Hyperplasia; Immune; Immune response; Immunoglobulin A; In Vitro; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Intestines; Knock-out; Knockout Mice; Leukocytes; Mediating; Modeling; Mucositis; Mucous Membrane; Mus; Peritonitis; Permeability; Phagocytosis; Phenotype; Play; Protein Family; Proteins; Recovery; Regulation; Research; Rest; Role; Secondary to; Series; Small Interfering RNA; System; T-Lymphocyte; Tight Junctions; United States National Institutes of Health; Zymosan; cell type; immune function; in vivo; junctional adhesion molecule; knockout animal; monolayer; mouse development; neutrophil; public health relevance; research study; response; salmonella colitis; therapeutic target

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.

描述（由申请人提供）：对通知号（NOT-OD-09-058）的回应，通知标题：NIH宣布可获得竞争性修订申请的恢复资金。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。连接粘附分子（JAM）蛋白家族已被证明调节上皮紧密连接功能和白细胞迁移。我们的研究结果表明JAM蛋白在肠黏膜炎症的病理生理中发挥重要作用，如在IBD中观察到的。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，可能会导致观察到的表型。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为解剖上皮细胞和白细胞JAM-A对粘膜通透性和肠道炎症的重要贡献提供手段。我们的初步结果表明JAM-A在调节肠道PMN募集中起重要作用，详细的发现与代偿性b细胞增生一致，这可能保护这些动物在面对结肠通透性大量增加时免于发生自发性结肠炎。这些观察结果表明，JAM-A通过直接调节白细胞功能和间接调节结肠上皮通透性，在肠道稳态中发挥核心作用。对这些发现进行进一步的研究显然是有必要的，并且可能会显著增强我们对JAMs与粘膜稳态之间关系的理解，更广泛地说，是对粘膜免疫功能基本调节的理解。