Dysbiosis in Hirschsprung Associated Enterocolitis Pathogenesis

先天性巨结肠相关小肠结肠炎发病机制中的生态失调

基本信息

批准号：
10341176
负责人：
Ankush Gosain
金额：
$ 41.04万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10341176
关键词：
Acetylcholine Affect Animals Antibiotics Automobile Driving Bacteria Cellular biology Cessation of life Colitis Complication Congenital Megacolon Data Development Disease Down-Regulation Endocrinology Endothelin B Receptor Enteric Nervous System Enterocolitis Epithelial Cells Etiology Exclusion Functional disorder Gnotobiotic Goals Host Defense Human Immune Evasion Immunoglobulin A Immunoglobulins Impairment Incidence Infant Inflammatory Bowel Diseases Intestinal Motility Intestinal Obstruction Intestines Laboratories Lactobacillus Lactobacillus plantarum Large Intestine Life Methodology Modeling Morbidity - disease rate Mus Neural Crest Neurotransmitters Newborn Infant Operative Surgical Procedures Outcome Study Pathogenesis Pathway interactions Patients Physiological Polymeric Immunoglobulin Receptors Postoperative Period Pre-Clinical Model Prevention approach Production Psychological reinforcement Publishing Research Rest Role Sampling Secretory Immunoglobulin A Small Intestines Testing Transgenic Animals acute symptom cell motility dysbiosis fecal transplantation gastrointestinal gut inflammation host microbiome improved innovation intestinal epithelium member microbial microbiome microbiota mortality motility disorder mouse model mutualism neurochemistry novel novel therapeutic intervention operation pathobiont receptor expression rectal spatiotemporal targeted treatment therapeutic target

项目摘要

Hirschsprung-associated enterocolitis (HAEC) is a life-threatening complication of Hirschsprung Disease (HSCR), a common cause of intestinal obstruction in the newborn that results from incomplete development of the enteric nervous system (ENS). HAEC affects 30-60% of infants with HSCR, occurs with unchanged incidence pre- and post-operatively, and carries a mortality of 5-10%, with the majority of deaths occurring in newborns prior to definitive operation. A critical barrier in the field is that the etiology of HAEC is poorly defined and current treatment remains empiric (bowel rest, rectal washouts, broad-spectrum antibiotics) and directed toward alleviating acute symptoms rather than targeting underlying pathophysiology. The long-term goal of our research is to define the pathophysiology of HAEC in order to develop novel therapeutic approaches that reduce morbidity and mortality in HSCR patients. Our preliminary and published findings, reinforced by those of other laboratories, support the central hypothesis that perturbation of host-microbiome mutualism, including evasion of immune exclusion and reinforcement of intestinal stasis by dysbiotic microbiota, drives the development of HAEC. Our objectives are to 1) define the mechanisms for impaired IgA production and secretion in HAEC, 2) identify the disease-promoting members of the dysbiotic HAEC microbiome, and 3) determine how the HAEC microbiome reinforces intestinal stasis. The proposed research is innovative because it will utilize novel, preclinical models to establish a causative relationship between dysbiosis and HAEC pathogenesis and test potential therapeutic targets. Our group is uniquely qualified to complete the aims because of our expertise in HSCR & HAEC, host- microbiome interactions, microbial endocrinology, and intestinal epithelial cell biology. The expected outcome of these studies will be a deeper understanding of the pathophysiology of HAEC and identification of novel therapeutic approaches for prevention or treatment of HAEC.

Hirschsprung相关的小肠结肠炎（HAEC）是威胁生命的Hirschsprung疾病的并发症（HSCR）是新生儿肠梗阻的常见原因，是由于不完整的发展而导致的肠神经系统（ENS）。 HAEC影响30-60％的HSCR婴儿，发生不变的发病率术前和术后，死亡率为5-10％，大多数死亡发生在新生儿中在确定操作之前。该领域的一个关键障碍是HAEC的病因较差，并且目前治疗仍然是经验性的（肠休息，直肠冲洗，广谱抗生素），并针对减轻急性症状，而不是靶向潜在的病理生理学。我们研究的长期目标是定义HAEC的病理生理学，以开发新的治疗方法来降低发病率和HSCR患者的死亡率。我们的初步和发表的发现，由其他实验室的发现，支持中心假设，即宿主 - 微生物组互助的扰动，包括逃避免疫不植物微生物群对肠道的排除和加强驱动HAEC的发展。我们的目标是1）定义HAEC中IGA生产和分泌受损的机制，2）确定促进疾病的成员HAEC微生物组和3）确定HAEC微生物组如何加强肠道滞留。拟议的研究具有创新性，因为它将利用新颖的临床前模型建立营养不良与HAEC发病机理和测试潜在治疗之间的致病关系目标。由于我们在HSCR和HAEC的专业知识，主持人 - 微生物组相互作用，微生物内分泌学和肠上皮细胞生物学。预期的结果这些研究将更深入地了解HAEC的病理生理学和新颖的鉴定预防或治疗HAEC的治疗方法。