Innate Immunity Driven Th1/Th2 bias in Leishmaniasis

利什曼病中先天免疫驱动的 Th1/Th2 偏差

• 批准号: 6931214
• 负责人: KEITH G NELSON
• 金额: $ 9.72万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6931214
• 关键词: Leishmania major; complement receptor; cytokine; gene targeting; genetically modified animals; helper T lymphocyte; immunity; immunologic receptors; laboratory mouse; leishmaniasis; macrophage; pathologic process; phagocytosis; polymerase chain reaction; protozoal antigen; tissue /cell culture; toll like receptor

DESCRIPTION (provided by applicant): The immediate goal of the candidate, Keith G. Nelson, DVM, is to complete a mentored training program in research of immunopathogenesis of Leishmania infection, which will culminate in both the PhD degree and continued postdoctoral study. Dr. Nelson's long-term goal is to become a principal investigator conducting research on the immune response to, pathogenesis and prevention of leishmaniasis and other vector-borne parasitic pathogens. The research-training program will be centered on the laboratory of Dr. Richard G. Titus, in the immunoparasitology Research Group at Colorado State University. The research environment has a strong history of extramural funding and biomedical scientist training. The candidate's training plan consists of laboratory and didactic instruction in contemporary molecular and immunological techniques and research methods applied to an animal model of leishmaniasis. The proposed research utilizes an established murine model of Leishmania infection to investigate the early stages of the immune response to Leishmania major(Lm) and subsequent Type 1 T cell vs. Type 2 T cell (Th1/Th2) differentiation, with a focus on the macrophage receptors and parasite surface antigens involved in host recognition and response. Three specific aims will be addressed: 1) to identify the macrophage complement and non-complement receptors involved in recognition, phagocytosis, and response to Lm, as well as characterizing changes in the Th1/Th2 response secondary to entry via specific macrophage receptors; 2) to characterize the role of toll-like receptors TLRs) in transducing host response to Lm infection, identifying relevant receptors and determining the effect on Th1/Th2 bias; 3) to determine the effect of major parasite surface molecules lipophosphoglycan (LPG) and gp63 on host recognition, phagocytosis and Th1/Th2 response to Lm. All of these will be addressed using in vivo infection of relevant knockout mice with LPG or gp63 deficient parasites, as well as with in vitro macrophage culture, receptor blocking, infection and co-cultivation with naive Th cells to assess functional priming. Cytokine profiles will be assessed via ELISA and RTPCR to determine Th1/Th2-associated bias and TLR mRNA will be assessed via RT-PCR. The results of these studies will provide new insights into the interactions between the primary phagocytic ceils of the innate immune response and the protozoan parasite Leishmania major. We will also gain insight into the effect of the innate immune response and pathogen recognition pathway on the establishment of Th1/Th2 responses in adaptive immunity. This information may prove to be important in the development of effective treatment, control and preventative measures in leishmaniasis, as well as furthering our knowledge of the interactions between the innate and adaptive arms of the immune system.

描述（由申请人提供）：候选人Keith G. Nelson， DVM，近期目标是完成一个在利什曼原虫感染免疫发病机制研究方面的指导培训计划，最终将获得博士学位和继续博士后研究。Nelson博士的长期目标是成为研究利什曼病和其他媒介传播的寄生虫病原体的免疫反应、发病机制和预防的首席研究员。这项研究培训计划将以科罗拉多州立大学免疫寄生虫学研究小组的理查德·g·提图斯博士的实验室为中心。研究环境在校外资助和生物医学科学家培训方面有着悠久的历史。候选人的培训计划包括实验室和教学指导，包括当代分子和免疫学技术以及应用于利什曼病动物模型的研究方法。