Cytokine signaling and IEC restitution in enteropathy: the Giardia paradigm

描述（由申请方提供）：蓝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%。G.兰伯氏菌感染是营养不良的综合症，营养不良是造成估计1/3儿童死亡和60%腹泻死亡的原因。田间试验表明，G.兰伯氏病与持续性腹泻有关，在某些人群中与儿童发育迟缓和发育受损有关。这项职业发展奖将使用新开发的持续性贾第虫病C57 B1/6小鼠模型来研究导致G.兰氏杆菌感染最近的研究表明，C57 B1/6菌株对G. Lamblia Assemblage B（H3）纯化的孢囊（Bartelt等人，JCI，2013）。感染加重蛋白质能量缺乏的营养不良，并与绒毛钝化有关。此外，蛋白质能量缺乏会改变小肠 尽管寄生虫负荷相似，但仍存在炎症反应（IL-4和IL-5 mRNA减弱以及B220+细胞相对减少）。总的来说，这些发现导致了一个假设，即在这种新的贾第鞭毛虫病和营养不良的小鼠模型中，G。肠病变通过肠道炎症和受损的上皮细胞稳态导致生长停滞。本项目将在体内评价（C57 B1/6; G. Lamblia纯化的H3包囊）引起的贾第鞭毛虫营养缺乏（血清游离氨基酸（HPLC）、矿物质和维生素），影响G.蓝氏病（使用目前的腹泻和营养不良的干预措施），以及重要的炎症介质和T细胞反应，改变上皮细胞的稳态和贾第虫病的生长。本提案中概述的职业发展计划将通过将研究生水平的课程工作与技术培训以及侧重于粘膜免疫学和肠道寄生虫感染的研讨会和会议相结合来提高该项目的成功。优秀的导师将提供实验专业知识和科学指导，为独立的临床医生-科学家的发展创造成功的环境。

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.