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

• 批准号: 10552703
• 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
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10552703
• 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; Immune Evasion; Immunoglobulin A; Immunoglobulins; Impairment; Incidence; Infant; Inflammatory Bowel Diseases; Intestinal Motility; Intestinal Obstruction; Intestines; Laboratories; Lactobacillus; Lactobacillus plantarum; Large Intestine; Life; Maps; Methodology; 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; Qualifying; Rectum; Research; Rest; Role; Sampling; Secretory Immunoglobulin A; Small Intestines; Surgical Models; 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

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.

先天性巨结肠相关性小肠结肠炎（HAEC）是先天性巨结肠病的一种危及生命的并发症 （HSCR）是新生儿肠梗阻的常见原因，由发育不完全引起， 肠神经系统（ENS）HAEC影响30-60%的HSCR婴儿，发生率不变 手术前和手术后，死亡率为5- 10%，大多数死亡发生在新生儿中 在最终手术之前。该领域的一个关键障碍是HAEC的病因学定义不清， 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是 是为了确定HAEC的病理生理学，以开发新的治疗方法，降低发病率 和HSCR患者的死亡率。我们的初步和已发表的研究结果，得到了其他实验室的支持， 支持了中心假设，即宿主-微生物组互惠关系的干扰，包括免疫逃避， 通过生态失调的微生物群排除和加强肠停滞，驱动HAEC的发展。我们 目的是：1）确定HAEC中IgA产生和分泌受损的机制，2）鉴定HAEC中IgA产生和分泌受损的机制， 微生态失调的HAEC微生物组的疾病促进成员，以及3）确定HAEC微生物组如何 加强肠道停滞。拟议的研究是创新的，因为它将利用新的，临床前模型 建立生态失调和HAEC发病机制之间的因果关系，并测试潜在的治疗方法， 目标的我们的团队是唯一有资格完成的目标，因为我们在HSCR和HAEC的专业知识，主机- 微生物组相互作用、微生物内分泌学和肠上皮细胞生物学。的预期成果 这些研究将是对HAEC的病理生理学的更深入的理解， 用于预防或治疗HAEC的治疗方法。