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: 10191178
• 负责人: Enid E. Martinez
• 金额: $ 18.92万
• 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/10191178
• 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/antagonist; 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.

项目概要/摘要 胃动力障碍影响 40-80% 的危重儿童，并且与显着的发病率和死亡率相关。 生命力。关于危重儿童胃动力障碍的机制存在知识空白， 限制该队列的治疗选择。胃肠道 (GI) 巨噬细胞调节胃运动和 已被证明其功能具有微生物组依赖性变化。微生物组依赖性变化 对巨噬细胞激活的影响是由微生物产物的跨上皮肠道运输介导的。连蛋白是 一种增加微生物产物跨上皮运输的蛋白质。连蛋白表达模型，包括- Zonulin 转基因小鼠 (Ztm) 存在菌群失调和促炎巨噬细胞激活的情况。在批评中—— 在表达连蛋白的病童中，我们在 Ztm 小鼠中发现了胃动力障碍。我们的中央hy- 假设是炎症条件下连蛋白上调，增加了跨上皮转运 来自改变的微生物组的微生物产物，可激活与胃动力障碍相关的巨噬细胞。 在目标 1 中，我们评估连蛋白介导的跨上皮肠道运输的增加是否是由于系统- ic炎症导致与胃动力障碍相关的巨噬细胞失调和激活。我们将 使用 Ztm 小鼠并使用 zonulin 抑制剂完成目标 1。在目标 2a 中，我们将识别 mi- 与胃动力相关的跨上皮肠道运输的微生物组组成和标记物 具有和不具有产生连蛋白的等位基因的患者。直接检查胃肠道巨噬细胞差异 钛是不可行的。因此，在目标 2b 中，我们采用了粪便材料移植的转化小鼠模型 来自目标 2a 中的患者，以检查有和没有 zonu 患者的微生物群是否存在差异 产生 lin 的等位基因和胃动力障碍导致小鼠巨噬细胞激活和胃动力障碍。 该提议填补了我们对危重疾病胃动力障碍机制理解的知识空白。 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。 加州疾病，这可能会影响该队列的临床结果。该提案详细介绍了一个为期四年的项目，其中 Martinez 博士将获得临床转化研究经验以及胃肠道生理学、粘膜免疫学方面的专业知识。 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 围绕理想的研究环境和与马丁内斯博士合作建立的指导团队将 准备她申请 NIH R01 补助金并促进她向独立学术迈进 职业。