Cytokine signaling and IEC restitution in enteropathy: the Giardia paradigm

描述（由申请人提供）：兰氏贾第鞭毛虫是一种普遍存在的肠道原生动物寄生虫，是2岁以下儿童中最常见的分离肠道病原体之一，在某些人群中累积发病率高达90%。兰氏螺旋体感染与营养不良同时发生，营养不良导致约三分之一的儿童死亡和60%的腹泻死亡。实地研究表明，兰氏螺旋体与持续性腹泻有关，在一些人群中，与儿童发育迟缓和发育受损有关。该职业发展奖将使用新开发的C57Bl/6持久性贾第虫小鼠模型来研究导致兰氏贾第虫感染后生长受损的机制。最近的研究发现，C57Bl/6菌株在受到兰氏杆菌组合B （H3）纯化的囊肿攻击后，对持续感染很敏感（Bartelt等）。江森自控,2013)。感染加重了蛋白质-能量缺乏的营养不良，并伴有绒毛变钝。此外，蛋白质能量缺乏会改变小肠

DESCRIPTION (provided by applicant): Giardia lamblia is a ubiquitous intestinal protozoan parasite that one of the most commonly isolated enteric pathogens in children less than 2 years old, reaching up to 90% cumulative incidence in some populations. G. lamblia infections are syndemic with malnutrition, the latter of which is responsible for an estimated 1/3 of childhood deaths and 60% of deaths due to diarrhea. Field studies demonstrate that G. lamblia associates with persistent diarrhea, and in some populations there is correlation with childhood stunting and impaired development. This career development award will use a newly developed C57Bl/6 murine model of persistent giardiasis to investigate mechanisms that lead to impaired growth following G. lamblia infection. Recent work has identified that the C57Bl/6 strain is susceptible t persistent infection following challenge with G. lamblia Assemblage B (H3) purified cysts (Bartelt, et al. JCI, 2013). Infection accentuates malnutrition in protein-energy deficiency, and associates with villus blunting. Furthermore, protein-energy deficiency alters the small intestinal inflammatory response (blunted IL-4 and IL-5 mRNA and relative diminishment of B220+ cells), despite a similar parasite burden. Collectively, these findings have led to the hypothesis that in this novel murine model of giardiasis and malnutrition, G. lamblia -enteropathy leads to growth faltering through intestinal inflammation and impaired epithelial cell homeostasis. This project will evaluate in vivo (C57Bl/6; G. lamblia purified H3 cysts) the resultant nutrient deficiencies i giardiasis (serum free amino acids (HPLC), minerals, and vitamins), the nutritional factors that influence G. lamblia disease (using current interventions for diarrhea and malnutrition), and the important inflammatory mediators and T-cell responses that alter epithelial cell homeostasis and growth in giardiasis. The outlined career development plan in this proposal will enhance the success of this project by combining graduate level course work with technical training and seminars and conferences focusing on mucosal immunology and enteric parasitic infections. Excellent mentorship will provide experimental expertise and scientific guidance creating a successful environment for the development of an independent clinician-scientist.