Evolution of Dendritic Cell Dysfunction in FIV Infection

描述(由申请人提供)：候选人Tracy Lynne Lehman，DVM的直接目标是完成一个研究逆转录病毒免疫调节和发病机制的指导计划，最终获得博士学位并发展成为一名独立的研究人员。雷曼博士的长期目标是成为一名首席研究员，负责研究针对动物和人类疾病的免疫调节策略。研究培训计划将集中在猫逆转录病毒研究实验室，该实验室由科罗拉多州立大学的发起人爱德华·A·胡佛博士指导。该实验室在外部资金和医学科学家培训方面有着良好的记录。候选人的培训计划包括应用于逆转录病毒免疫缺陷动物模型的当代细胞和免疫病毒学研究方法的实验室和教学指导。这项拟议的研究使用猫免疫缺陷病毒(FIV)模型来检查慢病毒感染的免疫反应，特别是评估FIV对髓系树突状细胞(MDCS)的影响。我们将致力于三个具体目标：(1)确定FIV感染猫骨髓来源的MDC功能改变的时间进程和机制，(2)确定体外操作FIV感染猫的骨髓来源MDC能否恢复功能并抑制病毒复制，以及(3)确定FIV感染对FIV感染猫的自体MDC治疗的影响。在目标1中，我们将通过评估TLR配体诱导的细胞因子、干扰素调节因子和转录调节因子的产生以及丝裂原活化蛋白激酶ERK和p38的激活来确定FIV感染如何影响BM来源的MDC功能。在目的2中，我们将观察改变IL-12、IL-10和转化生长因子-β三种免疫调节细胞因子和阻断吲哚胺2，3-双加氧酶对DC功能和病毒复制的影响。然后，在目标3中，我们将研究FIV对体内DC的影响。通过这些研究，我们希望进一步了解宿主对感染的反应，并评估干预病毒诱导的免疫损伤的方法。FIV模型非常适合于在慢病毒感染的整个过程中评估这种过程，并将实验室结果应用于治疗试验。这些信息可能导致开发各种疾病的有效疗法，包括人类免疫缺陷病毒感染。

DESCRIPTION (provided by applicant): The immediate goal of the candidate, Tracy Lynne Lehman, DVM, is completion of a mentored program investigating retrovirus immunoregulation and pathogenesis, culminating in a PhD degree and development towards an independent research career. Dr. Lehman's long-term goal is to become a principal investigator conducting research on immunomodulatory strategies against diseases of animals and humans. The research training program will be centered in the Feline Retrovirus Research Laboratory directed by sponsor Dr. Edward A. Hoover at Colorado State University. The laboratory has a strong record of extramural funding and medical scientist training. The candidate's training plan involves laboratory and didactic instruction in contemporary cellular and immunological virology research methods applied to an animal model of retroviral immunodeficiency. The proposed research examines the immune response to lentiviral infection using the feline immunodeficiency virus (FIV) model, specifically evaluating the effects of FIV on myeloid dendritic cells (mDCs). We will address three specific aims: (1) to determine the time course and mechanisms of altered bone marrow (BM)-derived mDC function in FIV-infected cats, (2) to determine whether ex vivo manipulation of BM-derived mDCs from FIV-infected cats can restore function and suppress viral replication in vitro, and (3) to determine the effects of FIV infection on autologous mDC therapy in FIV- infected cats. In Aim 1 we will determine how FIV infection affects BM-derived mDC function through evaluation of TLR ligand-induced cytokine, interferon regulatory factor, and transcriptional regulator production and activation of the mitogen activated protein kinases ERK and p38. In Aim 2 we will evaluate the effects of altering three immunoregulatory cytokines, IL-12, IL-10, and TGF-beta, and of blocking indoleamine 2,3-dioxygenase on DC function and viral replication in vitro. Then in Aim 3 we will investigate the effects of FIV on DCs in vivo. With these studies we hope to further our understanding of the host response to infection and evaluate methods of interfering with virus-induced immune impairment. The FIV model is ideal for the evaluation of such processes during the entire course of lentiviral infection and the application of laboratory results to therapeutic trials. This information could lead to the development of effective therapeutics for a variety of diseases, including human immunodeficiency virus infection in humans.