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.

先天性巨结肠相关小肠结肠炎 (HAEC) 是先天性巨结肠的一种危及生命的并发症 (HSCR)，新生儿肠梗阻的常见原因，是由于肠道发育不完全造成的肠神经系统（ENS）。 HAEC 影响 30-60% 患有 HSCR 的婴儿，但发生率没有变化术前和术后，死亡率为 5-10%，其中大多数死亡发生在新生儿中在最终操作之前。该领域的一个关键障碍是 HAEC 的病因尚不明确且目前尚不明确治疗仍然是经验性的（肠道休息、直肠冲洗、广谱抗生素）并针对缓解急性症状而不是针对潜在的病理生理学。我们研究的长期目标旨在定义 HAEC 的病理生理学，以开发降低发病率的新治疗方法和 HSCR 患者的死亡率。我们的初步和已发表的研究结果得到其他实验室的证实，支持宿主-微生物组互利共生的扰动，包括逃避免疫的中心假设通过失调微生物群排除和强化肠道瘀滞，推动了 HAEC 的发展。我们的目标是 1) 确定 HAEC 中 IgA 产生和分泌受损的机制，2) 确定失调的 HAEC 微生物组中促进疾病的成员，以及 3) 确定 HAEC 微生物组如何强化肠瘀。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生态失调与 HAEC 发病机制之间的因果关系并测试潜在的治疗方法目标。由于我们在 HSCR 和 HAEC 方面的专业知识，我们的团队拥有独特的资格来完成这些目标，微生物组相互作用、微生物内分泌学和肠上皮细胞生物学。预期结果这些研究将更深入地了解 HAEC 的病理生理学并鉴定新的预防或治疗HAEC的治疗方法。