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。 HAEC 影响 30-60% 患有 HSCR 的婴儿死亡率为 5-10%，其中大多数死亡发生在最终手术前的新生儿中。该领域的一个关键障碍是 HAEC 的病因尚不清楚，并且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），旨在减轻急性症状，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定义病理生理学 HAEC 并开发新的治疗方法来降低 HSCR 患者的发病率和死亡率。我们的先前的研究和其他小组的研究，利用 HSCR/HAEC 小鼠模型以及人类 HSCR/HAEC 患者样本显示，菌群失调与 HAEC 的发生有关，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。尽管几乎唯一的焦点都放在肠道细菌（微生物组）上，其他微生物界也有助于多样化的肠道群落，包括真菌酵母和霉菌（真菌组），但这些在很大程度上已被被忽视了。在这里，我们建议重点研究粘膜屏障反应，包括 IgA/IgG 和上皮防御，针对 HSCR/HAEC 患者和小鼠疾病特定组织中的真菌病原体。我们的中央假设对真菌病原体的异常粘膜免疫反应会引发 HAEC 炎症剧集。我们的目标是 1) 确定失调的 HAEC 真菌组中促进疾病的成员 2) 定义对真菌病原体的正常和 HAEC 粘膜免疫反应，以了解病因触发器和目标。我们正在通过协同和长期合作来解决这个问题 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研究建立真菌群失调与 HAEC 发病机制之间因果关系的模型。我们的由于我们在 HSCR/HAEC、宿主病原体方面的专业知识，我们的团队具有独特的资格来完成这些目标相互作用、知生菌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 病理生理学并确定预防或治疗的新靶点 HAEC。