The Fibrosis-Immunity Interface in Corneal Transplantation

项目摘要/摘要 目前的建议是一项为期五年的综合培训方案，旨在培养一名 职业生涯致力于了解T细胞免疫和角膜纤维化之间的关系。 我在移植免疫学和眼科专科方面有很强的研究背景 角膜方面的培训，对角膜纤维化有临床兴趣。作为一种先进的临床和研究角膜 做弥撒的人。眼耳科和哈佛医学院，我一直在继续我的角膜移植工作 免疫学，证明在角膜移植的T细胞介导的免疫排斥反应中存在纤维化。 我们的初步数据表明，在角膜移植中，T细胞在促进 肌成纤维细胞的形成和纤维化，而肌成纤维细胞反过来又能够调节同种异体反应性T细胞 功能。这些数据为目前的研究方案奠定了基础，在该方案中，我们将调查 角膜移植中的纤维化-免疫界面。在具体目标1中，我们将定义关键机制 通过哪些效应T细胞促进纤维化并评估这些机制的调节是否可以预防 体内纤维化和移植失败。在具体目标2中，我们将定义关键机制， 肌成纤维细胞抑制效应器T细胞以恢复免疫稳态。拟议研究的目标是 研究这些基本机制，并最终开发新的治疗策略 器官移植中移植物纤维化的预防和T细胞免疫抑制。 Reza Dana博士，世界角膜免疫学专家，长期从事角膜免疫学研究 临床医生-科学家的发展将作为我的主要导师，我还将得到 由美国国立卫生研究院资助的独立科学家组成的顾问团队，每个人都在 指导年轻的研究人员。拟议的研究和职业发展方案将在#年进行。 谢彭斯眼科研究所/马萨诸塞州眼耳医院和哈佛医学院，以及我 将充分利用这些机构的大量资源。 我致力于作为一名临床医生兼科学家的职业生涯，总体目标是将我的 对解决患者未得到满足的需求的新方法进行基础科学调查。K08助学金 这里详述的提案涉及一个重要的和以前未被探索的角膜病理生理学领域 同时还为我提供了成为一名 独立的临床医生兼科学家。

PROJECT SUMMARY/ABSTRACT The present proposal is a comprehensive five-year training program for the development of an academic career focused on understanding the relationship between T cell immunity and fibrosis in the cornea. I have a strong research background in transplantation immunology and sub-specialty ophthalmology training in cornea, with a clinical interest in corneal fibrosis. As an Advanced Clinical and Research Cornea Fellow at Mass. Eye and Ear and Harvard Medical School, I have continued my work in corneal transplantation immunology, demonstrating the presence of fibrosis in T cell-mediated immune rejection of corneal transplants. Our preliminary data suggest that in corneal transplantation, T cells play a direct role in promoting myofibroblast formation and fibrosis, and that myofibroblasts are in turn capable of regulating alloreactive T cell function. This data has laid the foundation for the current research proposal in which we will investigate the fibrosis-immunity interface in corneal transplantation. In Specific Aim 1 we will define the critical mechanisms by which effector T cells promote fibrosis and evaluate whether modulation of these mechanisms can prevent fibrosis and transplant failure in vivo. In Specific Aim 2 we will define the critical mechanisms by which myofibroblasts suppress effector T cells to restore immune homeostasis. The goal of the proposed research is to investigate these fundamental mechanisms and ultimately develop novel therapeutic strategies for the prevention of graft fibrosis and suppression of T cell immunity in organ transplantation. Dr. Reza Dana, a world expert in corneal immunology with a long track-record of fostering the career development of clinician-scientists will serve as my primary mentor, and I will additionally have the support of an advisory team composed of independent NIH-funded scientists, each with extensive experience in mentoring young researchers. The proposed research and career development programming will take place at the Schepens Eye Research Institute/Massachusetts Eye and Ear Infirmary and Harvard Medical School, and I will have full access to the significant resources of these institutions. I am committed to a career as a clinician-scientist, with the over-arching goal being to translate my basic science investigations into novel approaches for addressing the unmet needs of patients. The K08 grant proposal detailed here addresses an important and previously unexplored area of corneal pathophysiology while simultaneously providing me the mentorship, resources and academic foundation needed to become an independent clinician-scientist.