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

• 批准号: 9185102
• 负责人: Luther A Bartelt
• 金额: $ 10.33万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 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/9185102
• 关键词: Cytokine; signaling; IEC; restitution; enteropathy

DESCRIPTION (provided by applicant): This is an application for a Career Development Award (K08) for Luther Bartelt, MD. Dr. Bartelt is an Infectious Disease Fellow at the University of Virginia in the Division of Infectious Diseases and International Health. His research is being conducted under the mentorship of Dr. Richard L. Guerrant, MD, FIDSA, Thomas H. Hunter Professor of International Medicine in Infectious Diseases and International Health at the University of Virginia School of Medicine. Dr. Guerrant is a recipient of the Infectious Disease Society of America Mentor Award, and has mentored more than 150 students and fellows during his career. The proposed project will be executed at the University of Virginia in the newly constructed Carter Harrison Medical Science Building with more than 100,000 net square feet of research space and access to state of the art facilities for animal research and molecular equipment. Dr. Bartelt is pursuing a career as a physician-scientist focusing on enteric infections that contribute to environmental enteropathy, an exceedingly common cause of childhood malnutrition. His immediate goal is to gain expertise in the pathogenesis of the ubiquitous protozoan pathogen G. lamblia as a cause of growth failure. G. lamblia infection occurs in up to 90% of children and in some populations associates with malnutrition. Field investigations of the impact of G. lamblia have reached a state of equipoise, with findings demonstrating protection from acute diarrhea but increased risk of persistent diarrhea. This project will utiliz a novel C57Bl/6 murine model of persistent giardiasis to investigate mechanisms that lead to impaired growth following G. lamblia infection. This work builds on Dr. Bartelt's discovery that the C57Bl/6 strain is susceptible to persistent infection following challenge with G. lamblia H3 purified cysts. It is innovative, as no other investigators have recently published a model of persistent Giardia and malnutrition interactions. Giardia-infected mice develop impaired growth, a phenotype that is accelerated during concomitant malnutrition. The hypothesis tested is that G. lamblia impairs intestinal epithelial cell (IEC) proliferation and differentiation, and that compensatory adaptive host mucosal defenses are necessary for IEC restitution. Preliminary data shows that malnourished-infected mice have blunted villi and diminished crypt proliferation compared to nourished-infected controls. Furthermore, malnourished mice have diminished tissue IL4 and IL5 responses to infection. Collectively, these findings have led to the hypothesis that in this novel murine model of giardiasis and malnutrition, ineffective intestinal epithelial ell (IEC) proliferation leads to growth failure, and that IL4-related host mucosal responses are protective. This project will define early epithelial cell responses to G. lamblia H3 in vivo, inducer signaling molecules in the epithelial compartment during early and established G. lamblia H3 infection, the cellular and mucosal molecular aberrations caused by malnutrition in response to G. lamblia, and will define the role of IL4 for IEC proliferation during early and established giardiasis as compared to alternative cytokine-mediated pathways. The findings will advance knowledge of G. lamblia pathogenesis and mucosal defenses to enteric pathogens that promote enteropathy in general. The outlined career development plan is inclusive of graduate level courses on immunology and cellular biology and complementary laboratory workshops that will enhance both knowledge and technical skills in this field. Furthermore, the career development plan includes a certificate course in Faculty Development, which in combination with the research project will provide a solid foundation for transition to an independent researcher and mentor. Excellent mentorship along with a supportive environment with a well-proven track record will provide experimental expertise and scientific guidance. RELEVANCE: G. lamblia is a globally ubiquitous pathogen that associates with persistent diarrhea and is syndemic with malnutrition. This research will identify mechanisms whereby G. lamblia induces growth failure. The focus will be on the role of host mucosal defenses that facilitate epithelial cell proliferation. The results will be useful for improving strategies for mucosal repair in malnourished children and enteric diseases in general.

描述（由申请人提供）：这是一个职业发展奖（K 08）路德巴特尔特，医学博士的应用程序。Bartelt博士是弗吉尼亚大学传染病和国际卫生部的传染病研究员。他的研究是在理查德·L. Guerrant，MD，FIDSA，托马斯H.弗吉尼亚大学医学院传染病和国际卫生国际医学亨特教授。Guerrant博士是美国传染病学会导师奖的获得者，在他的职业生涯中指导了150多名学生和研究员。拟议的项目将在弗吉尼亚大学新建的卡特·哈里森医学科学大楼内执行，该大楼拥有超过10万平方英尺的研究空间，并可使用最先进的动物研究和分子设备设施。 博士巴特尔特正在追求作为一个医生科学家的职业生涯，专注于肠道感染，有助于环境肠病，一个非常常见的原因，儿童营养不良。他的近期目标是获得普遍存在的原生动物病原体G. Lamblia作为生长失败的原因。G.在高达90%的儿童中发生兰布拉感染，并且在某些人群中与营养不良有关。田间调查表明，G.蓝氏菌已达到平衡状态，研究结果表明，对急性腹泻有保护作用，但持续性腹泻的风险增加。本项目将利用一种新的持续性贾第虫病C57 B1/6小鼠模型来研究导致贾第虫病后生长受损的机制。兰氏杆菌感染这项工作建立在Bartelt博士的发现基础上，即C57 B1/6菌株在G. Lamblia H3纯化的包囊。这是创新的，因为没有其他研究人员最近发表了持续贾第虫和营养不良相互作用的模型。 感染贾第虫的小鼠生长受损，这是一种在伴随营养不良期间加速的表型。检验的假设是G.蓝氏菌损害肠上皮细胞（IEC）增殖和分化，且代偿性适应性宿主粘膜防御对于IEC恢复是必需的。初步数据显示，与受感染的对照组相比，受感染的小鼠绒毛变钝，隐窝增殖减少。此外，营养不良的小鼠对感染的组织IL 4和IL 5反应减弱。总的来说，这些发现导致了一个假设， 在贾第虫病和营养不良新鼠模型中，无效的肠上皮细胞（IEC）增殖导致生长失败，且IL 4相关的宿主粘膜应答是保护性的。本项目将确定早期上皮细胞对G. Lamblia H3的细胞内，在早期和建立的G. Lamblia H3感染，营养不良引起的细胞和粘膜分子畸变。Lamblia，并将定义IL 4在早期和建立贾第鞭毛虫病期间与替代的精氨酸介导的途径相比对IEC增殖的作用。这一发现将进一步加深对G. Lamblia致病机理和对促进一般肠病的肠道病原体的粘膜防御。概述的职业发展计划包括免疫学和细胞生物学的研究生课程以及补充实验室研讨会，这些研讨会将提高这一领域的知识和技术技能。此外，职业发展计划包括教师发展证书课程，与研究项目相结合，将为过渡到独立研究员和导师提供坚实的基础。优秀的指导沿着一个支持性的环境与良好的记录将提供实验的专业知识和科学指导。 相关性：G.兰氏杆菌是一种全球普遍存在的病原体，与持续性腹泻有关，并且是营养不良的综合征。这项研究将确定的机制，G。Lamblia诱导生长失败。重点将放在促进上皮细胞增殖的宿主粘膜防御的作用上。研究结果将有助于改善营养不良儿童和一般肠道疾病的粘膜修复策略。