Evolution of Dendritic Cell Dysfunction in FIV Infection

候选人Tracy Lynne Lehman，DVM的近期目标是完成一个指导计划 研究逆转录病毒免疫调节和发病机制，最终获得博士学位， 走向独立的研究生涯。雷曼博士的长期目标是成为首席研究员 开展针对动物和人类疾病的免疫调节策略研究。的 研究培训计划将集中在申办者指导的猫逆转录病毒研究实验室 博士Edward A.胡佛在科罗拉多州立大学。该实验室有很强的校外记录， 资金和医学科学家培训。候选人的培训计划包括实验室和教学 当代细胞和免疫病毒学研究方法应用于动物的指令 逆转录病毒免疫缺陷模型。这项研究旨在检测对慢病毒的免疫反应， 使用猫免疫缺陷病毒（FIV）模型，特别是评估FIV对 骨髓树突状细胞（mDC）。我们将讨论三个具体目标：（1）确定时间进程， FIV感染猫的骨髓（BM）来源的mDC功能改变的机制，（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FIV感染的猫的功能。 体外病毒复制，以及（3）确定FIV感染对FIV中自体mDC治疗的影响- 被感染的猫在目标1中，我们将确定FIV感染如何影响BM衍生的mDC功能， 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评价 有丝分裂原活化蛋白激酶ERK和p38的产生和活化。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的作用， 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，并评估干扰病毒诱导的免疫损伤的方法。FIV 该模型是评价慢病毒感染整个过程中这些过程的理想模型， 将实验室结果应用于治疗试验。这些信息可能会导致发展 有效治疗多种疾病，包括人类免疫缺陷病毒感染。

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 researchexamines 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 indolamine 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.