Cytokine signaling and IEC restitution in enteropathy: the Giardia paradigm

肠病中的细胞因子信号传导和 IEC 恢复：贾第鞭毛虫范例

基本信息

批准号：
9055636
负责人：
Luther A Bartelt
金额：
$ 18.45万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-15 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9055636
关键词：
2 year old Advisory Committees Amino Acids Arginine Biological Assay CD4 Positive T Lymphocytes Cell physiology Cells Cessation of life Child Child health care Childhood Chronic Cognitive Cyst Cytokine Signaling Development Development Plans Diarrhea Diet Disease Enteral Environment Epithelial Epithelial Cells Failure Flow Cytometry Foundations Giardia Giardia lamblia Giardiasis Growth High Pressure Liquid Chromatography Homeostasis Host Defense Immune Immune response Immunology Immunotherapy Incidence Infection Inflammation Inflammation Mediators Inflammatory Inflammatory Response Inflammatory disease of the intestine Interleukin-4 Interleukin-5 Intervention Intestinal Diseases Intestines K-Series Research Career Programs Knowledge Lead Life Malabsorption Syndromes Malnutrition Measures Mediator of activation protein Mentors Mentorship Messenger RNA Metronidazole Micronutrients Minerals Modeling Mucositis Mus NG-Nitroarginine Methyl Ester Nutrient Nutritional Outcome PTPRC gene Parasites Parasitic infection Pathogenesis Pathology Pathway interactions Pharmacologic Substance Population Protein Deficiency Proteins Research Research Personnel Role Scientist Serum Serum zinc level result Signal Pathway Small Intestines Splenocyte T cell response Technology Testing Therapeutic Intervention Training Translational Research United States National Institutes of Health Universities Villus Vitamins Work Zinc Zinc deficiency career development clinical investigation cognitive development cytokine defense response dietary restriction enteric pathogen experience extracellular field study improved in vivo insight mouse model neutralizing antibody novel nutrient absorption pathogen public health relevance repaired response success symposium uptake

项目摘要

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.

描述（由申请人提供）：贾第鞭毛虫是无处不在的肠道原生动物寄生虫，是不到2岁的儿童中最常见的肠道病原体之一，在某些人群中达到90％的累积发生率。 G. Lamblia感染与营养不良是集合的，后者是估计1/3的儿童死亡和60％因腹泻而导致的死亡。现场研究表明，G。Lamblia与持续的腹泻相关，在某些人群中，与儿童发育迟缓和发育受损相关。该职业发展奖将使用新开发的C57BL/6鼠模型的持续贾第鞭毛疾病模型来研究导致G.兰布利亚感染后增长受损的机制。最近的工作表明，在与G. lamblia组合B（H3）纯化的囊肿挑战之后，C57BL/6菌株是易感的T持续感染（Bartelt等人，JCI，2013年）。感染加剧了蛋白质能力缺乏的营养不良，并与绒毛钝化相关。此外，蛋白质能缺乏改变了小肠尽管寄生虫负担相似，但炎症反应（钝化IL-4和IL-5 mRNA以及B220+细胞的相对减少）。总的来说，这些发现导致了以下假设：在这种新颖的贾第鞭毛病和营养不良的鼠模型中，G。Lamblia-肠病导致生长通过肠道炎症和上皮细胞稳态受损而动摇。该项目将评估体内（C57BL/6; G. lamblia纯化H3囊肿）由此产生的营养缺乏症I贾第鞭毛疾病（无血清氨基酸（HPLC），矿物质和维生素），养分因素，使用了目前的limblia疾病（使用肠道疾病）和营养不良的养分（使用尿素疾病） T细胞的反应改变了上皮细胞稳态和贾第鞭毛疾病的生长。该提案中概述的职业发展计划将通过将研究生级课程的工作与技术培训以及针对粘膜免疫学和肠胃寄生虫感染的研讨会和会议相结合，从而提高该项目的成功。优秀的指导将提供实验专业知识和科学指导，为独立临床医生的发展创造一个成功的环境。