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项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为独立的研究生涯。Lehman博士的长期目标是成为一名首席研究员，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，由申办者Edward A.胡佛在科罗拉多州立大学。该实验室在校外资助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当代细胞和免疫病毒学研究方法应用于逆转录病毒免疫缺陷动物模型的实验室和教学指导。拟议的研究使用猫免疫缺陷病毒（FIV）模型检查对慢病毒感染的免疫反应，特别是评估FIV对骨髓树突状细胞（mDC）的影响。我们将解决三个具体目标：（1）确定FIV感染的猫中骨髓（BM）衍生的mDC功能改变的时间过程和机制，（2）确定来自FIV感染的猫的BM衍生的mDC的离体操作是否可以恢复功能并抑制体外病毒复制，以及（3）确定FIV感染对FIV感染的猫中自体mDC疗法的影响。在目的1中，我们将通过评价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有丝分裂原活化蛋白激酶ERK和p38的活化来确定FIV感染如何影响BM衍生的mDC功能。在目标2中，我们将评估改变三种免疫调节细胞因子IL-12、IL-10和TGF-β以及阻断吲哚胺2，3-双加氧酶对体外DC功能和病毒复制的影响。然后在目的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，并评估干扰病毒诱导的免疫损伤的方法。FIV模型非常适合在慢病毒感染的整个过程中评估这些过程，并将实验室结果应用于治疗试验。这一信息可能导致开发有效的治疗各种疾病，包括人类免疫缺陷病毒感染的人类。

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.