Modulation of the Intestinal Immune Response in Necrotizing Enterocolitis

坏死性小肠结肠炎肠道免疫反应的调节

• 批准号: 10468084
• 负责人: MISTY L GOOD
• 金额: $ 34.57万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10468084
• 关键词: Adult; Anti-Inflammatory Agents; Attenuated; Biological Models; Biology; Breast Feeding; CD4 Positive T Lymphocytes; Cause of Death; Cell Culture Techniques; Cell Differentiation process; Cells; Confocal Microscopy; Cytometry; Data; Defect; Derivation procedure; Development; Devices; Disease; Engineering; Epithelial; Epithelial Cells; Evolution; Excision; Gastrointestinal Diseases; Genes; Goals; Goblet Cells; Host Defense; Immune; Immune response; Immune system; Immunology; In Vitro; Infant; Inflammation; Inflammatory; Inflammatory Response; Interleukin Receptor; Interleukin-17; Intestines; Ischemic Bowel Disease; Knowledge; Laboratories; Lamina Propria; Lymphocyte; Lymphocytic Infiltrate; Mediating; Microfluidics; Modeling; Morbidity - disease rate; Mucous Membrane; Mus; Necrosis; Necrotizing Enterocolitis; Operative Surgical Procedures; Pathogenesis; Pathogenicity; Pathologic; Pathway interactions; Phenotype; Play; Predisposition; Premature Birth; Premature Infant; Premature Infant Diseases; Prevention; Prevention strategy; Recombinant Interleukins; Regulation; Research; Resolution; Risk; Role; Secretory Cell; Severities; Signal Pathway; Signal Transduction; Small Intestines; Stem Cell Development; Supportive care; Survivors; Testing; Therapeutic; antimicrobial; base; cytokine; design; dysbiosis; graft vs host disease; gut inflammation; gut microbiota; high risk; high risk infant; human model; in vitro Model; in vivo; innovation; interleukin-22; intestinal epithelium; intestinal injury; intravital microscopy; mortality; mouse model; multidisciplinary; neonatal mice; next generation sequencing; novel; novel therapeutic intervention; prevent; protective effect; receptor; resistin; response; stem cell differentiation; stem cell function; stem cell self renewal; stem cells; therapeutic target; wound healing

Project Summary/Abstract    Necrotizing enterocolitis (NEC) is the leading cause of death from gastrointestinal disease in premature infants  and is characterized by an uncontrolled inflammatory response. The lack of understanding of the mechanisms  that regulate the vicious inflammatory cascade, the inability to determine which infants are susceptible to NEC  and a lack of therapeutic targets all contribute to the persistently high mortality rate. The goals of the  proposed research are to determine the mechanisms that regulate the pathologic immune response  during NEC and use this knowledge to design novel epithelial-­or immune-­specific strategies for this  devastating disease. Our laboratory has recently discovered that the interleukin-­22 (IL-­22) signaling pathway  plays a critical role in attenuating the inflammatory response during NEC, as mice lacking the receptor for IL-­22  (IL-­22Ra1) on the intestinal epithelium demonstrate accelerated mortality in a neonatal mouse model of NEC-­ like intestinal injury. We demonstrate that mice subjected to experimental NEC develop gross evidence of  small intestinal ischemia and necrosis, that can be completely rescued in mice with intact IL-­22 signaling by  administering recombinant IL-­22. In seeking to determine the mechanisms mediating this protection, we have  demonstrated that treatment with recombinant IL-­22 decreases the pro-­inflammatory Th17 lymphocytic  infiltrate, which we have shown contributes to NEC pathogenesis. Furthermore, we also determined that IL-­22  signaling is important in the regulation of intestinal stem cell differentiation, as mice deficient in IL-­22Ra1 in the  intestine demonstrate an abnormally profound phenotype characterized by decreased numbers of secretory  cells in the intestine as well as decreased expression of critical genes involved in intestinal stem cell  development and host defense. Based on these findings, we hypothesize that IL-­22 signaling through the  receptor IL-­22Ra1 attenuates NEC by 1) enhancing intestinal stem cell function, 2) increasing goblet cell  differentiation and 3) shifting the immune cell repertoire towards an anti-­inflammatory phenotype. We will  complete our aims of this project by bringing together a multi-­disciplinary team with expertise in epithelial  biology, mucosal immunology, mass cytometry, next-­generation sequencing, high-­resolution confocal and  intravital microscopy as well as microfluidics and engineering for the derivation of in vitro models of human  intestinal function using gut-­on-­a-­chip devices. These studies will make a significant conceptual advance in  understanding the signaling pathways involved in attenuating NEC, explaining the unique susceptibility of the  premature infant to NEC based on a defect in IL-­22 signaling, and we will evaluate a novel therapeutic strategy  for NEC by introducing the anti-­inflammatory cytokine IL-­22 in the intestinal milieu.

项目总结/文摘

项目成果

Essentials of neonatal-perinatal medicine fellowship: scholarship perspective.

• DOI: 10.1038/s41372-021-00957-3
• 发表时间: 2022-04
• 期刊: Journal of perinatology : official journal of the California Perinatal Association
• 作者: Bauserman M;Vasquez M;Chess PR;Carbajal M;ONTPD Fellowship Directors Writing Group;Good M
• 通讯作者: Good M

Opportunities for the federal government to advance necrotizing enterocolitis research.

联邦政府有机会推进坏死性小肠结肠炎研究。

• DOI: 10.1038/s41390-020-1081-5
• 发表时间: 2020
• 期刊: Pediatric research
• 影响因子: 3.6
• 作者: Gadepalli,SamirK;Canvasser,Jennifer;Good,Misty;Raju,TonseNK
• 通讯作者: Raju,TonseNK