Evaluating the effect of zonulin-mediated intestinal trafficking on gastrointestinal macrophages and their function on gastric motility

评估连蛋白介导的肠道运输对胃肠道巨噬细胞的影响及其对胃动力的功能

• 批准号: 10670640
• 负责人: Enid E. Martinez
• 金额: $ 5.4万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-14 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10670640
• 关键词: Advanced Development; Affect; Alleles; Clinical; Critical Care; Critical Illness; Critically ill children; Endotoxins; Enteric Nervous System; Environment; Epithelial; Exposure to; Gastrointestinal Physiology; Goals; Grant; Immunology; Inflammation; Inflammatory; Injections; Intestines; Knowledge; Lipopolysaccharides; Macrophage Activation; Mediating; Mentors; Modeling; Morbidity - disease rate; Mucous Membrane; Mus; Operative Surgical Procedures; Outcome; Patient Recruitments; Patients; Phenotype; Physicians; Postoperative Period; Proteins; Protocols documentation; Research; Research Personnel; Scientist; Secondary to; Stomach; System; Therapeutic; Transgenic Mice; Translational Research; Transplant Recipients; Transplantation; United States National Institutes of Health; Up-Regulation; Wild Type Mouse; Work; base; care outcomes; career; cell motility; cohort; diagnostic biomarker; dysbiosis; experience; gastrointestinal; gut microbiome; host microbiome; improved; inhibitor; intestinal epithelium; macrophage; microbial; microbiome; microbiome alteration; microbiome composition; microbiota; mortality; motility disorder; mouse model; multidisciplinary; novel; novel diagnostics; novel therapeutics; patient subsets; skills; therapeutic target; therapy development; trafficking; translational approach; zonulin

Project Summary/ Abstract Gastric dysmotility affects 40-80% of critically ill children and is associated with significant morbidity and mor- tality. There are knowledge gaps regarding the mechanisms for gastric dysmotility in critically ill children, which limit the therapeutic options for this cohort. Gastrointestinal (GI) macrophages regulate gastric motility and have been shown to have microbiome-dependent changes on their function. Microbiome-dependent changes on macrophage activation are mediated by trans-epithelial intestinal trafficking of microbial products. Zonulin is a protein that increases trans-epithelial trafficking of microbial products. Models of zonulin expression, includ- ing a Zonulin transgenic mouse (Ztm), have dysbiosis and activation of pro-inflammatory macrophages. In criti- cally ill children who express zonulin and in Ztm mice we have identified gastric dysmotility. Our central hy- pothesis is that zonulin upregulation under conditions of inflammation, increases trans-epithelial trafficking of microbial products from an altered microbiome which activate macrophages associated with gastric dysmotility. In Aim 1 we evaluate whether zonulin-mediated increases in trans-epithelial intestinal trafficking due to system- ic inflammation result in dysbiosis and activation of macrophages associated with gastric dysmotility. We will complete Aim 1 with Ztm mice and the use of a zonulin inhibitor. In Aim 2a, we will identify differences in mi- crobiome composition and markers of trans-epithelial intestinal trafficking in relation to gastric motility in pa- tients with and without the zonulin-producing allele. Direct examination of GI macrophage differences in pa- tients is not feasible. Therefore, in Aim 2b, we employ a translational mouse model of fecal material transplant from patients in Aim 2a to examine whether differences in microbiota from patients with and without the zonu- lin-producing allele and gastric dysmotility result in macrophage activation and gastric dysmotility in the mice. This proposal fills a knowledge gap in our understanding of mechanisms for gastric dysmotility in critical illness. Our long-term goal is to identify novel diagnostic markers and therapeutic targets for gastric dysmotility in criti- cal illness, which can impact clinical outcomes for this cohort. This proposal details a four-year project in which Dr. Martinez will gain experience in clinical-translational research and expertise in GI physiology, mucosal im- munology, host-microbiome interactions and the neuro-enteric system. These educational opportunities, the surrounding ideal research environment and established mentoring team that is working with Dr. Martinez will prepare her to apply for a NIH R01 grant and promote her advancement towards an independent academic career.

项目总结/摘要 胃动力障碍影响40-80%的重症儿童，并与显著的发病率和莫尔的 总体。关于危重病患儿胃动力障碍的机制存在知识空白， 限制了该队列的治疗选择。胃肠道（GI）巨噬细胞调节胃运动， 已显示其功能具有微生物组依赖性变化。微生物组依赖性变化 对巨噬细胞活化的影响是由微生物产物的跨上皮肠道运输介导的。佐努林是 一种增加微生物产物跨上皮运输的蛋白质。连蛋白表达的模型，包括- 使用Zonulin转基因小鼠（Ztm），具有生态失调和促炎巨噬细胞活化。在关键- 在表达zonulin的癌症儿童中，我们已经确定了Ztm小鼠的胃动力障碍。我们的中央卫生- 假设在炎症条件下，连蛋白上调，增加了细胞的跨上皮运输， 来自改变的微生物组的微生物产物，其激活与胃动力障碍相关的巨噬细胞。 在目的1中，我们评估是否zonulin介导的增加跨上皮肠运输由于系统， IC炎症导致与胃动力障碍相关巨噬细胞的生态失调和活化。我们将 用Ztm小鼠完成Aim 1和使用zonulin抑制剂。在目标2a中，我们将确定不同之处， 胃动力相关的跨上皮肠运输的crobiome组成和标记物， 有和没有产生zonulin等位基因的个体。直接检查胃肠道巨噬细胞的差异， 这是不可行的。因此，在目标2b中，我们采用粪便物质移植的转化小鼠模型 目的2a中的患者，以检查来自具有和不具有小带的患者的微生物群的差异， 产生LIN的等位基因和胃动力障碍导致小鼠中的巨噬细胞活化和胃动力障碍。 这一建议填补了我们对危重病胃动力障碍机制的认识空白。 我们的长期目标是确定危重患者胃动力障碍的新诊断标志物和治疗靶点， CAL疾病，这可能会影响该队列的临床结局。该提案详细介绍了一个为期四年的项目， 博士Martinez将获得临床转化研究的经验和GI生理学，粘膜免疫学， 免疫学、宿主-微生物组相互作用和神经肠系统。这些教育机会， 周围理想的研究环境和建立指导团队，是与马丁内斯博士将 准备她申请美国国立卫生研究院R 01补助金，并促进她走向独立的学术进步 事业