Hormonal Modulation of DCs: Influences on Innate and Adaptive Immunity

简介（由申请人提供）：Dr. Papenfuss, d.v.m.， M.S.在她的临床培训期间表现出对生物医学研究的持续承诺。她在D.V.M.培训期间获得了硕士学位，并完成了解剖病理学的住院医师培训，目前是兽医病理生物学博士学位的候选人，预计将于2006年春季毕业。Papenfuss博士通过研究与自身免疫性疾病模型实验性自身免疫性脑脊髓炎（EAE）相关的激素的免疫调节作用，在比较病理学、免疫学和疾病的免疫发病机制方面获得了专业知识。EAE是多发性硬化症（ms）的动物模型，不仅是了解自身免疫性疾病的重要模型，而且是了解许多疾病的基本免疫机制的有力工具。树突状细胞（dc）是免疫系统的细胞，驱动炎症并显著影响由此产生的免疫反应的特征。因此，它们是广泛的炎症或免疫介导的疾病（如自身免疫、传染病、过敏和肿瘤）的有效治疗靶点。最近的数据确定了一种新的激素调节树突状细胞群，显示出强大的免疫调节能力（即reg- dc）。总体研究目标是研究激素环境如何产生reg- dc，这些reg- dc如何影响炎症和辅助性T细胞发育，并使用动物模型EAE确定这些reg- dc的治疗潜力。目的1将评估reg- dc的表型和功能特征，并确定激素环境下reg- dc影响适应性免疫反应和EAE的能力。Aim 2确定共刺激分子（PD-L1、PD-L2）、可溶性因子（即IL-10、吲哚胺2,3-双加氧酶、IL-12和TNF-ot）对reg- dc促进EAE保护作用的相对贡献，Aim 3将确定雌激素受体在reg- dc生成中的作用。环境：研究将在实验室内进行，并在发起人Caroline Whitacre博士的指导下进行，Caroline Whitacre博士是基础免疫学、T细胞生物学和EAE领域公认的专家。这项工作将在分子病毒学、免疫学和医学遗传学以及兽医生物科学部门内进行。这两个部门的综合资源，加上俄亥俄州立大学研究人员的合作环境，以及Whitacre博士和俄勒冈州立大学同事提供的广泛合作，将为Papenfuss博士在生物医学研究界提供许多合作的可能性。SERCA的资助将允许Papenfuss博士全身心地投入到研究培训中，促进她发展成为一名独立的科学家，并实现她成为一名学术研究病理学家的终身职业目标。

DESCRIPTION (provided by applicant): Dr. Papenfuss, D.V.M., M.S. has demonstrated continued commitment to biomedical research during her clinical training. She completed an M.S. during her D.V.M. training, has completed a residency in Anatomic Pathology and is a candidate for a Ph.D. in veterinary pathobiology with an expected graduation date of Spring 2006. Dr. Papenfuss has gained expertise in comparative pathology, immunology and the immunopathogenesis of disease by investigating the immunomodulatory effects of hormones as they relate to the autoimmune disease model experimental autoimmune encephalomyelitis (EAE). EAE is an animal model for multiple sclerosis (M.S.) and is an important model for understanding not only autoimmune diseases, but serves as a powerful tool to understand fundamental immunological mechanisms underlying numerous diseases. Dendritic cells (DCs) are cells of the immune system that drive inflammation and dramatically influence the character of the resultant immune response. Thus, they are potent therapeutic targets in a broad range of inflammatory or immune- mediated disorders (e.g. autoimmunity, infectious diseases, allergy and oncology). Recent data identifies a novel population of hormonally modulated dendritic cells demonstrating potent immunoregulatory capabilities (i.e., reg-DCs). The overall research goals are to investigate how hormonal environments can produce reg-DCs, how these reg-DCs influence inflammation and helper T cell development and to determine the therapeutic potential of these reg-DCs using the animal model EAE. Aim 1 will evaluate phenotypic and functional characteristics of reg-DCs and determine the capacity of reg-DCs from hormonal environments to influence the adaptive immune response and EAE. Aim 2 determine the relative contributions of costimulatory molecules (PD-L1, PD-L2), soluble factors (i.e. IL-10, indoleamine 2,3-dioxygenase, IL-12 and TNF-ot) on how reg-DCs promote protection in EAE and Aim 3 will determine the role of estrogen receptors in the generation of reg-DCs. Environment: The research will be performed within the laboratory and under the guidance of the sponsor, Dr. Caroline Whitacre, a recognized expert in fundamental immunology, T cell biology and EAE. The work will be conducted within the Departments of Molecular Virology, Immunology and Medical Genetics and Veterinary Biosciences. The combined resources of these two departments, in conjunction with the collaborative environment of the researchers at the Ohio State University, and the extensive collaborations afforded by Dr. Whitacre and OSU colleagues, will afford Dr. Papenfuss numerous collaborative possibilities within the biomedical research community. The SERCA grant will permit Dr. Papenfuss to devote full time to research training, facilitate her development into an independent scientist and fulfill her lifelong career objectives of becoming an academic research pathologist.