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Defining non-genetic mechanisms that prevent death in a Hirschsprung disease mouse model

定义预防先天性巨结肠症小鼠模型死亡的非遗传机制

基本信息

批准号：
10624957
负责人：
ROBERT O HEUCKEROTH
金额：
$ 61.48万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-27 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10624957
关键词：
Affect Anatomy Bacteria Biological Assay Cause of Death Cell physiology Cessation of life Child Clinical Trials Colon Complex Congenital Abnormality Congenital Megacolon Constipation Dangerousness Data Defect Diet Dietary Component Disease Disease Outcome Disease model Distal Enteric Nervous System Enterocolitis Environment Epithelial Cells Epithelium Excision Exclusive Breastfeeding Failure Feces Food Functional disorder Genetic Germ-Free Goals Growth Human In Vitro Inbreeding Inflammation Institution Intestines Length Life Microbe Mucins Mucous body substance Mus Nervous System Nutrient Operative Surgical Procedures Outcome Pediatric Hospitals Philadelphia Positioning Attribute Postoperative Period Probiotics Property Proteins Quebec RNA Recurrence Risk Sepsis Severities Symptoms Testing Transition zone of anal mucous membrane Transplantation Universities Vomiting abdominal distension antimicrobial peptide beneficial microorganism candidate identification design fecal transplantation feeding gut inflammation gut microbes human data improved improved outcome in vivo innovation microbial mouse model mucosal microbiota non-genetic novel therapeutic intervention premature prevent small molecule

项目摘要

Project Summary: Our goal is to improve the lives of children with Hirschsprung disease (HSCR), a life- threatening birth defect where the enteric nervous system (ENS) is absent from the end of the bowel. Because the ENS regulates most aspects of bowel function, “aganglionic” bowel that lacks ENS does not work well. Symptoms include intractable constipation, bilious vomiting, abdominal distension, growth failure and HSCR- associated enterocolitis (HAEC). HAEC is the most dangerous problem because in addition to bowel inflammation, during HAEC, bacteria may move across the bowel epithelium causing sepsis that can be fatal. Primary treatment for HSCR is pull-through surgery to remove aganglionic bowel and re-attach ENS-containing bowel to near the anal verge. Unfortunately, ~35% of children continue to have problems after pull-through surgery, including HAEC. One long-standing mystery is why symptom onset and severity differ so much among children with HSCR. In particular, some children never have HAEC, but other children have repeated HAEC episodes before and after pull-through surgery. Length of aganglionosis, genetic differences, and surgical details undoubtedly impact HAEC risk and HSCR outcomes. The impact of non-genetic factors like diet, gut microbes and small molecules inside the bowel have barely been investigated in HSCR or in HSCR models. Using Piebald lethal sl/sl mice, a well-established HSCR model, we discovered a 5-fold difference in survival between two mouse facilities. The survival difference is not related to the length of aganglionic bowel, distinct genetics, or cause of death, and we do not perform surgery. Instead, the survival difference reflects fundamental aspects of HSCR pathophysiology that can be altered by non-genetic factors in the environment. We hypothesized that the 5-fold survival difference occurs because sl/sl mice are fed different types of food and have different bowel microbes at each institution. Differences in diet and gut microbes can alter small molecules within the bowel. Many small molecules including nutrients in food and microbial metabolites impact bowel barrier function in ways that affect sepsis risk. Aim 1 tests the hypothesis that diet and microbes affect survival by swapping diets fed to sl/sl at each institution, making germ-free mice, and performing fecal transplant into germ-free mice using stool from each institution. New preliminary data suggest that simply changing diet markedly alters survival in sl/sl mice. Aim 2 defines how the bowel barrier differs in sl/sl between institutions using anatomic and functional approaches and identifies microbes that cross bowel epithelium to cause sepsis. Aim 3 defines mucosa- associated microbes and small molecules within the bowel lumen that could affect barrier function. At the completion of this study we will know if diet or gut microbes can be manipulated to improve survival in HSCR models and will have defined mechanisms that alter sepsis risk. These data can then be leveraged to design human clinical trials to improve outcomes in children with HSCR and reduce HAEC occurrence.

项目概述：我们的目标是改善患有先天性巨结肠疾病（HSCR）的儿童的生活