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Modeling Host-Fungal Interactions in Hirschsprung-Associated Enterocolitis

先天性巨结肠相关小肠结肠炎中宿主-真菌相互作用的建模

基本信息

批准号：
10832933
负责人：
Ankush Gosain
金额：
$ 19.98万
依托单位：
UNIVERSITY OF COLORADO DENVER
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：
2021-06-09 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10832933
关键词：
Modeling Host Fungal Interactions Hirschsprung

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. HAEC affects 30-60% of infants with HSCR 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 and develop novel therapeutic approaches that reduce morbidity and mortality in HSCR patients. Our prior investigations and those of other groups, utilizing mouse models of HSCR/HAEC as well as human HSCR/HAEC patient samples, have associated a dysbiotic microbiota with the development of HAEC but have not directly tested causation or identified targetable molecular mechanisms to prevent or treat the disease. While almost exclusive focus has been placed on gut bacteria (microbiome), other microbial kingdoms contribute to the diverse intestinal community, including fungal yeast and molds (mycobiome), but these have largely been overlooked. Here, we propose a focused investigation of the mucosal barrier responses, including IgA/IgG and epithelial defense, to fungal pathogens in HSCR/HAEC patient and murine disease specific tissues. Our central hypothesis that aberrant mucosal immune responses to fungal pathobionts trigger HAEC inflammatory episodes. Our objectives are to 1) identify the disease-promoting members of the dysbiotic HAEC mycobiome and 2) define the normal and HAEC mucosal immune response to fungal pathobionts to understand etiological triggers and targets. We are approaching this problem through a synergistic and long-standing collaboration between the MPIs laboratories. The proposed research is innovative because it will utilize novel, preclinical models to establish a causative relationship between dysbiosis of the mycobiome and HAEC pathogenesis. Our group is uniquely qualified to complete the aims because of our expertise in HSCR/HAEC, host-pathogen interactions, gnotobiotic expertise, and mucosal immunology. The expected outcome of these studies will be a deeper understanding of HAEC pathophysiology and identification of novel targets 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），新生儿肠梗阻的常见原因。HAEC影响30-60%的HSCR婴儿并且具有5- 10%的死亡率，其中大多数死亡发生在最终手术之前的新生儿中。该领域的一个关键障碍是HAEC的病因学定义不明确，目前的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，而不是而不是针对潜在的病理生理学我们研究的长期目标是确定的HAEC和开发新的治疗方法，降低HSCR患者的发病率和死亡率。我们先前的研究和其他小组的研究，利用HSCR/HAEC的小鼠模型以及人类 HSCR/HAEC患者样品中的微生物群与HAEC的发展相关，但没有直接测试因果关系或确定预防或治疗疾病的靶向分子机制。而几乎所有的焦点都集中在肠道细菌（微生物组）上，其他微生物王国也有助于多种肠道群落，包括真菌酵母和霉菌（真菌生物群），但这些在很大程度上是忽视在这里，我们提出了一个重点调查的粘膜屏障反应，包括伊加/IgG和上皮防御，对HSCR/HAEC患者和鼠疾病特异性组织中的真菌病原体。我们的中央对真菌致病菌异常粘膜免疫应答触发HAEC炎性的假说情节。我们的目标是：1）确定有害HAEC菌群的致病成员和2）定义正常和HAEC粘膜对真菌致病生物的免疫应答，以了解病原学触发器和目标我们正在通过协同和长期合作来解决这个问题在MPI实验室之间。拟议的研究是创新的，因为它将利用新的，临床前建立真菌群落生态失调和HAEC发病机制之间的因果关系的模型。我们由于我们在HSCR/HAEC、宿主-病原体、相互作用，gnotobiotic专业知识，和粘膜免疫学。这些研究的预期结果将是更深入地了解HAEC的病理生理学，并确定预防或治疗HAEC的新靶点。港灯。