Mechanisms of IL-23 receptor-mediated pathogenicity in CD4+ T cells

项目总结/摘要 该提案提出了一项为期五年的研究职业发展计划，重点是研究 皮肤红斑狼疮（CLE）中CD 4 + T细胞上的IL-23受体（IL-23 R）。该候选人目前是 哈佛医学院皮肤科讲师，布里格姆大学皮肤科， 妇女医院。概述的提案建立在候选人以前的研究和临床经验的基础上 在分子和细胞免疫学和皮肤生物学中， Vijay Kuchroo博士的主要导师实验室内的技术。建议的实验和教学 工作将使候选人具有一套独特的跨学科技能，使他能够过渡到 作为自身免疫皮肤生物学的医生科学家的独立性。 皮肤受累是系统性红斑狼疮（SLE）的主要特征，SLE是一种全身性自身免疫性疾病， 疾病影响多个器官，但也可以发生在没有全身性疾病。皮肤狼疮 红斑狼疮（CLE）显著影响患者的生活质量，社会经济地位，并可导致 永久性疤痕和色素异常因此，迫切需要更有效的治疗方法。然而，在这方面， 我们目前对CLE发病机制的认识有限，使得靶向治疗的发展 难因此，患者护理可能会受到负面影响，因为最佳治疗方案无法 总是可以实现的。治疗可以改善皮肤，全身性疾病，两者兼而有之，或两者都没有。因此， 重要的是，更好地了解CLE发病机制的基本免疫学基础， 以满足这一临床需求。本研究旨在探讨IL-23 R表达对CD 4 + T细胞的作用， 细胞在CLE的发展。拟议的项目将直接解决这一重要问题，同时克服 目前在外地的限制。目的1将研究IL-23 R赋予致病性的机制， CD 4 + T细胞。目的2测试IL-23 R是否赋予CD 4 + T细胞致病性，然后其可以驱动 红斑狼疮小鼠模型中自发性皮肤炎症。Aim 3利用尖端基因组 技术和分析，以鉴定CLE中新的、转录上不同的、致病性CD 4 + T淋巴细胞 皮肤损伤总的来说，该项目结合了传统的分子和细胞方法， 基因组技术和分析，以解决皮肤自身免疫性疾病中严重未满足的需求。

Project Summary/Abstract This proposal presents a five year research career development program focused on the study of the role of the IL-23 receptor (IL-23R) on CD4+ T cells in cutaneous lupus erythematosus (CLE). The candidate is currently an Instructor in Dermatology at Harvard Medical School in the Department of Dermatology at the Brigham and Women's Hospital. The outlined proposal builds upon the candidate's previous research and clinical experience in molecular and cellular immunology and cutaneous biology by leveraging the use of emerging genomic technologies within Dr. Vijay Kuchroo's, his primary mentor's, laboratory. The proposed experiments and didactic work will position the candidate with a unique set of cross disciplinary skills that will enable him to transition to independence as a physician scientist in autoimmune cutaneous biology. Cutaneous involvement is a major feature of systemic lupus erythematosus (SLE), a systemic autoimmune disease affecting multiple organs, but can also occur in the absence of systemic disease. Cutaneous lupus erythematosus (CLE) significantly impacts patients' quality of life, socioeconomic status, and can result in permanent scarring and dyspigmentation. Therefore, more effective therapies are critically required. However, our current understanding of CLE pathogenesis is limited, making the development of targeted therapies difficult. As a consequence, patient care can be negatively impacted as optimal treatment regimens cannot always be achieved. Therapies can improve the skin, systemic disease, both, or neither. Therefore, it is of critical importance that a better understanding of the basic immunologic underpinnings of CLE pathogenesis be achieved to meet this clinical need. This proposal aims to investigate the role of IL-23R expression on CD4+ T cells in the development of CLE. The proposed project will directly address this vital question while overcoming current limitations in the field. Aim 1 will examine the mechanisms by which the IL-23R confers pathogenicity to CD4+ T cells. Aim 2 tests whether the IL-23R confers pathogenicity to CD4+ T cells, which can then drive spontaneous skin inflammation in a mouse model of lupus erythematosus. Aim 3 leverages cutting edge genomic technologies and analysis to identify novel, transcriptionally distinct, pathogenic CD4+ T lymphocytes in the CLE lesional skin. Taken together, this project combines traditional molecular and cellular approaches with emerging genomic technologies and analysis to address a critically unmet need in cutaneous autoimmune disease.