Cytokine signaling and IEC restitution in enteropathy: the Giardia paradigm

描述(申请人提供)：蓝氏贾第鞭毛虫是一种普遍存在的肠道原虫寄生虫，是2岁以下儿童最常见的肠道病原体之一，在一些人群中累积发病率高达90%。蓝氏菌感染与营养不良并存，后者造成了估计三分之一的儿童死亡和60%的腹泻死亡。现场研究表明，兰氏革兰氏菌与持续性腹泻有关，在某些人群中，与儿童发育迟缓和发育障碍有关。该职业发展奖将使用新开发的C57BL/6小鼠持续性贾第鞭毛虫病模型来研究感染革兰氏原虫后导致生长受损的机制。最近的工作已经证实，C57BL/6菌株在攻击革兰氏菌组合B(H3)纯化的包囊后对持续感染敏感(Bartelt等人)。JCI，2013)。感染加剧了蛋白质-能量缺乏的营养不良，并与绒毛钝化有关。此外，蛋白质-能量缺乏改变了小肠 炎症反应(IL-4和IL-5mRNA减弱，B220+细胞相对减少)，尽管有类似的寄生虫负担。总而言之，这些发现导致了一种假设，即在这个新的贾第虫病和营养不良的小鼠模型中，兰氏革兰氏菌肠病通过肠道炎症和受损的上皮细胞稳态导致生长停滞。该项目将在体内评估(C57BL/6；蓝氏贾第鞭毛虫纯化的H3包囊)导致的营养缺乏，贾第鞭毛虫病的营养缺乏(血清游离氨基酸、矿物质和维生素)，影响蓝氏贾第鞭毛虫疾病的营养因素(使用目前针对腹泻和营养不良的干预措施)，以及改变贾第虫病上皮细胞动态平衡和生长的重要炎症介质和T细胞反应。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侧重于粘膜免疫学和肠道寄生虫感染的技术培训和研讨会和会议相结合，加强该项目的成功。优秀的导师将提供实验专业知识和科学指导，为独立临床医生-科学家的发展创造一个成功的环境。

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.