Modeling Host-Fungal Interactions in Hirschsprung-Associated Enterocolitis

先天性巨结肠相关性小肠结肠炎(HAEC)是先天性巨结肠的一种危及生命的并发症 (HSCR)，这是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%，大多数死亡发生在最终手术前的新生儿。 该领域的一个关键障碍是HAEC的病因尚不明确，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)，旨在缓解急性症状，而不是 而不是瞄准潜在的病理生理学。我们研究的长期目标是定义病理生理学 并开发新的治疗方法，降低HSCR患者的发病率和死亡率。我们的 先前的研究和其他组的研究，使用HSCR/HAEC的小鼠模型和人类 HSCR/HAEC患者样本，与HAEC的发展相关的非生物微生物区系，但有 没有直接测试病因或确定有针对性的分子机制来预防或治疗疾病。而当 几乎只把重点放在肠道细菌(微生物组)上，其他微生物王国有助于 不同的肠道群落，包括真菌酵母和霉菌(真菌生物群)，但这些在很大程度上 被忽视了。在这里，我们建议重点研究粘膜屏障反应，包括IgA/Ig G和 上皮防御，对HSCR/HAEC患者和小鼠疾病特异性组织中的真菌病原体。我们的中央 对真菌致病菌的异常粘膜免疫反应触发HAEC炎症的假说 剧集。我们的目标是：1)鉴定HAEC真菌生态组的致病成员 2)明确正常和HAEC黏膜对真菌病原菌的免疫反应，以了解病原学 触发点和目标。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。这项拟议的研究具有创新性，因为它将利用新的、临床前的 建立真菌菌群失调与HAEC发病机制之间因果关系的模型。我们的 集团是唯一有资格完成目标的人，因为我们在HSCR/HAEC，宿主-病原体方面的专业知识 相互作用、诺生菌专业知识和粘膜免疫学。这些研究的预期结果将是 加深对HAEC病理生理学的了解，确定防治HAEC的新靶点 HAEC。

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.