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.

Hirschsprung相关的小肠结肠炎（HAEC）是威胁生命的Hirschsprung疾病的并发症（HSCR），这是新生儿肠梗阻的常见原因。 HAEC影响了30-60％的HSCR婴儿并具有5-10％的死亡率，大部分死亡发生在确定性手术之前的新生儿中。该领域的关键障碍是HAEC的病因定义很差，并且当前的治疗仍然存在经验性（肠休息，直肠冲洗，广谱抗生素），并致力于缓解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病理生理学 HAEC并开发出新的治疗方法，以降低HSCR患者的发病率和死亡率。我们的先前的研究和其他群体的研究，利用HSCR/HAEC的小鼠模型以及人类 HSCR/HAEC患者样本已将不植物菌群与HAEC的发展相关联未直接测试因果关系或鉴定出可预防或治疗疾病的目标分子机制。尽管几乎独家的重点已放在肠道细菌（微生物组）上，其他微生物王国有助于多样化的肠道社区，包括真菌酵母和霉菌（Mycobiome），但在很大程度上是被忽视。在这里，我们提出了对粘膜屏障反应的重点调查，包括IgA/IgG和上皮防御，用于HSCR/HAEC患者和鼠类疾病特定组织的真菌病原体。我们的中心假设对真菌病原体的异常粘膜免疫反应触发HAEC炎症情节。我们的目标是1）确定失调HAEC MYCOBIOME的促进疾病成员 2）定义对真菌病原体的正常和HAEC粘膜免疫反应以了解病因触发和目标。我们正在通过协同和长期的合作来解决这个问题在MPI实验室之间。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了霉菌组的营养不良与海克发病机理之间的致病关系。我们的由于我们在HSCR/HAEC，宿主病原体方面的专业知识，因此团体具有独特的资格来完成目标相互作用，gnotobiotic专业知识和粘膜免疫学。这些研究的预期结果将是对HAEC病理生理学的更深入了解和对预防或治疗的新目标的鉴定 haec。