Antigen presentation to the adaptive immune system in the choroid contributes to ocular autoimmune disease

项目总结： 该项目的总体目标是将首席研究员(PI)发展成为一名独立的临床医生- 在眼睛自身免疫领域做出贡献的科学家。PI已经获得了神经科学博士学位，探索 适应性免疫系统在轴突损伤模型中的作用。他还接受过额外的临床培训 眼科和葡萄膜炎和眼免疫学的专科训练，这构成了他的医学基础 在圣路易斯华盛顿大学眼科和视觉科学系实习。这个 这里概述的五年职业发展计划将利用教学课程的组合，个性化 来自专家合作者的培训，以及来自知名调查人员的指导，以增强他的知识 基础，学习他可以在他的职业生涯中继续使用的新的实验模型，并定义研究 他将以这些问题为基础开始他的独立研究计划。在节目结束时，他 将获得成为独立调查员所需的技能。 他的主要导师是Rajendra Apte，医学博士，R01资助的研究员，有纵向记录 培训早期调查人员，这些调查人员已经成为富有成效的独立职业。他是一位杰出的 脉络膜免疫领域的学者，并具有强大的临床科学家背景，这将对 帮助PI应对过渡到独立实验室所涉及的挑战。阿普特博士将得到支持 由世界领先的实验性自身免疫性葡萄膜炎专家雷切尔·卡斯皮博士、乔纳森·基普尼斯博士、 在边缘组织的适应性免疫系统方面的顶级专家，以及Gregory Wu，医学博士，最近的K08 中枢神经系统自身免疫奖获得者和专家。私家侦探将利用他的导师委员会和 华盛顿大学充满活力的科学环境，世界一流的医学研究之一 机构，以发展脉络膜适应性免疫反应这一未被探索的课题。 葡萄膜炎是可预防失明的主要原因之一，尽管许多工作都在评估 在T细胞衍生的细胞因子的作用方面，对免疫的解剖学认识有很大差距 反应包括适应性免疫系统与眼部抗原的接口。这一赤字导致了 作为主要治疗手段的有毒且往往无效的系统疗法。我们证明了眼内抗原 被脉络膜吸收，这是一种具有丰富适应性免疫存在的组织。自身免疫性葡萄膜炎中有 脉络膜中CD4+T细胞的增加，表明脉络膜作为免疫接口起着至关重要的作用 眼内空间和适应性免疫系统之间的关系。在这个提案中，我们将检验假设 适应性免疫系统是由脉络膜中的视网膜抗原激活的，这种相互作用在 在葡萄膜炎中的作用。我们将进一步阐明脉络膜免疫监视的机制。 了解这一过程背后的机制对诊断的发展具有广泛的意义 测试和靶向治疗将改善葡萄膜炎的临床结果。

Project summary: The overarching goal of this project is to develop the principal investigator (PI) into an independent clinician- scientist contributing to the field of ocular autoimmunity. The PI has obtained his PhD in neuroscience, exploring the roles of the adaptive immune system in axonal injury models. He has additional clinical training in ophthalmology and subspecialty training in uveitis and ocular immunology, which forms the basis for his medical practice in the Department of Ophthalmology and Visual Sciences at Washington University in St. Louis. The five-year career development plan outlined here will utilize a combination of didactic courses, individualized training from expert collaborators, and mentorship from established investigators to enhance his knowledge base, to learn new experimental models he can continue to use in his career, and to define the research questions on which he will base the start of his independent research program. By the end of this program, he will have acquired the skills necessary to become an independent investigator. His primary mentor is Rajendra Apte, MD PhD, an R01-funded investigator who has a longitudinal track record of training early-stage investigators that have gone on to productive independent careers. He is a preeminent scholar in the field of choroidal immunity and has a strong background as a clinician scientist that will be vital for helping the PI navigate the challenges involved in transitioning to an independent lab. Dr. Apte will be supported by Rachel Caspi, PhD, the world-leading expert in experimental autoimmune uveitis, Jonathan Kipnis, PhD, the foremost expert in the adaptive immune system in border tissues, and Gregory Wu, MD PhD, a recent K08 awardee and expert on CNS autoimmunity. The PI will take advantage of his mentorship committee and the vibrant scientific environment of Washington University, one of the world’s premiere medical research institutions, to develop the unexplored topic of the adaptive immune response in the choroid. Uveitis is one of the leading causes of preventable blindness, and while much work has gone in to evaluating the effects of T cell-derived cytokines, there is a significant gap in understanding of the anatomy of the immune response including where the adaptive immune system interfaces with ocular antigens. This deficit has led to toxic and often ineffective systemic therapies as the mainstay of treatment. We show that intraocular antigens are taken up in the choroid, a tissue that has a rich adaptive immune presence. In autoimmune uveitis there is an increase of CD4+ T cells in the choroid, indicating that the choroid plays a vital role as the immune interface between the intraocular space and adaptive immune system. In this proposal, we will test the hypothesis that the adaptive immune system is activated by retinal antigens in the choroid and that this interaction plays a central role in uveitis. We will further elucidate the mechanisms contributing to immune surveillance in the choroid. Understanding the mechanisms behind this process has broad implications in the development of diagnostic testing and targeted therapy that will improve the clinical outcomes in uveitis.