Elucidating the Role of Regulatory T cells in Protecting Epithelial Stem Cell Niches

项目摘要/摘要 该提案描述了一项为期5年的研究和职业发展计划，该计划将使Jarish Cohen博士能够 实现他的长期目标，成为一名独立资助的内科医生兼科学家，研究如何监管T 细胞(Treg)在发育、动态平衡和疾病期间保护皮肤上皮干细胞。目前， 皮肤常驻免疫细胞用来保护皮肤上皮干细胞的机制知之甚少 炎症性皮肤病和脱发的细胞。拟议的研究将集中于揭示 Tregs保护毛囊干细胞免受自身反应性T细胞攻击的机制。科恩博士 已经产生了一种新的体内实验模型，即Treg介导的HFSC保护免受自身免疫攻击， 这与一种高度病态的人类疤痕脱发非常相似。此外，他还开创了一种高度 创新的局部技术，删除特定于皮肤驻留的Treg基因，这将使他能够解决 Treg介导的干细胞免疫保护的器官特异性机制。在目标1中，科恩博士将澄清 Treg介导的HFSC保护作用的时空动力学及对皮肤Treg作用机制的剖析 定位于HFSC利基市场。目标2将侧重于阐明Tregs在皮肤中的不同机制 和淋巴结被用来防止HFSC的破坏。在《目标3》中，科恩博士将利用 全面的转录和尖端成像技术来识别分子和途径 人类瘢痕性脱发的Treg功能障碍和Treg定位模式的改变。聚合数据将 为我们理解树突状细胞如何促进上皮干细胞的免疫耐受提供了一个重要的进步 细胞，并有可能确定治疗人类皮肤病的新治疗策略。 他在加州大学旧金山分校(UCSF)从事博士后工作并担任临床讲师 皮肤病理学服务，科恩博士在战略上寻求额外的培训和指导 皮肤免疫学。在迈克尔·罗森布鲁姆博士的指导下，医学博士，博士，皮肤刺激专家 生物，候选人，共同导师(Jason Cyster博士和Ophir Klein博士，医学博士)和科学 顾问(鲍里斯·巴斯蒂安博士，医学博士，博士和阿布·阿巴斯医学博士，博士)发展了自己的职业发展 科恩博士计划在最先进的免疫学和尖端成像方面获得更多经验 技术、生物统计学、上皮干细胞生物学和科学交流。为了加强科恩博士的 培训，一个由导师、科学顾问和贾扬塔博士组成的多学科咨询委员会 加州大学旧金山分校病理学系主任、医学博士Debnath将每两年举行一次会议，审查他的进展和 支持他的事业发展。拟议的培训方案利用联合国系统的综合资源 Rosenblum实验室、加州大学旧金山分校免疫学培训计划和加州大学旧金山分校皮肤科 和病理学。这将为科恩博士向独立研究人员的转变提供理想的环境。

PROJECT SUMMARY/ABSTRACT This proposal describes a 5-year research and career development plan that will enable Dr. Jarish Cohen to achieve his long-term goal of becoming an independently funded physician-scientist studying how regulatory T cells (Tregs) protect cutaneous epithelial stem cells during development, homeostasis, and disease. Currently, very little is known about the mechanisms skin-resident immune cells use to safeguard cutaneous epithelial stem cells in inflammatory dermatoses and alopecias. The proposed research will focus on uncovering the mechanisms by which Tregs protect hair follicle stem cells (HFSC) from attack by autoreactive T cells. Dr. Cohen has generated a novel experimental in vivo model of Treg-mediated protection of HFSC from autoimmune attack, that closely resembles a highly morbid form of human scarring alopecia. Additionally, he has pioneered a highly innovative topical technique to delete genes specifically in skin-resident Tregs, which will allow him to resolve organ-specific mechanisms of Treg-mediated immunoprotection of stem cells. In Aim 1, Dr. Cohen will elucidate the spatial and temporal kinetics of Treg-mediated HFSC protection and dissect the mechanism of skin Treg localization to the HFSC niche. Aim 2 will focus on elucidation of the distinct mechanisms that Tregs in the skin and lymph nodes employ to safeguard against HFSC destruction. In Aim 3, Dr. Cohen will leverage comprehensive transcriptomic and cutting-edge imaging technologies to identify molecules and pathways of Treg dysfunction and altered patterns of Treg localization in human scarring alopecias. The aggregate data will provide a major advancement in our understanding of how Tregs promote immune tolerance of epithelial stem cells and have the potential to identify novel therapeutic strategies to treat human dermatoses. During his post-doctoral work and as a Clinical Instructor in the University of California, San Francisco (UCSF) Dermatopathology Service, Dr. Cohen has strategically sought out additional training and mentorship in cutaneous immunology. Under the mentorship of Dr. Michael Rosenblum, M.D., Ph.D., an expert in skin Treg biology, the candidate, co-mentors (Drs. Jason Cyster, Ph.D., and Ophir Klein, M.D., Ph.D.), and scientific advisors (Drs. Boris Bastian, M.D., Ph.D., and Abul Abbas M.D., Ph.D.) have developed a career development plan for Dr. Cohen to gain additional experience in state of the art immunology and cutting-edge imaging techniques, biostatistics, epithelial stem cell biology, and scientific communication. To enhance Dr. Cohen's training, a multidisciplinary advisory committee consisting of mentors, scientific advisors, and Dr. Jayanta Debnath, M.D., chair of the UCSF Department of Pathology, will meet biannually to review his progress and support his career development. The proposed training program draws on the combined resources of the Rosenblum Laboratory, the UCSF Immunology Training Program, and the UCSF Departments of Dermatology and Pathology. This will provide an ideal setting for Dr. Cohen's transition to an independent investigator.