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

阐明调节性 T 细胞在保护上皮干细胞生态位中的作用

• 批准号: 10523621
• 负责人: Jarish Newman Cohen
• 金额: $ 17.59万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10523621
• 关键词: Advisory Committees; Affinity; Alopecia; Antigens; Autoimmune; Autoimmunity; Biology; Biometry; CD8-Positive T-Lymphocytes; CTLA4 gene; California; Cell Communication; Cells; Cicatrix; Clinical; Communication; Cutaneous; Cytoprotection; Data Aggregation; Dermatology; Dermatopathology; Development; Development Plans; Disease; Dissection; Doctor of Medicine; Doctor of Philosophy; Epidermis; Exhibits; FOXP3 gene; Formalin; Functional disorder; Funding; Genes; Goals; Growth; Hair; Hair follicle structure; Homeostasis; Human; I-antigen; IL2RA gene; Image Analysis; Imaging Techniques; Imaging technology; Immune; Immune Tolerance; Immune mediated destruction; Immune response; Immunological Models; Immunologics; Immunology; Immunosuppression; Incidence; Inflammation; Inflammatory; Injury; Interleukin 2 Receptor; Interleukin-10; Interleukin-2; Investigation; Kinetics; Laboratories; Lymphocyte; Mammals; Mediating; Mentors; Mentorship; Molecular; Multiplexed Ion Beam Imaging; Mus; Natural regeneration; Organ; Paraffin Embedding; Pathology; Pathway interactions; Patients; Pattern; Phase; Physicians; Play; Population; Postdoctoral Fellow; Process; Proliferating; Proteins; Regulatory T-Lymphocyte; Research; Research Personnel; Resources; Role; San Francisco; Scientist; Services; Skin; Skin Physiology; Techniques; Testing; Tissues; Training; Training Programs; Transforming Growth Factor beta; Universities; Water; Work; analysis pipeline; autoimmune pathogenesis; autoreactive T cell; career; career development; cell injury; chemokine; draining lymph node; epithelial stem cell; epithelium regeneration; experience; experimental study; human disease; immunoregulation; in vivo Model; innovation; insight; instructor; keratinocyte; lymph nodes; mouse model; multidisciplinary; multimodality; neoplastic; novel; novel therapeutic intervention; pathogen; prevent; research and development; secondary lymphoid organ; self-renewal; single-cell RNA sequencing; skin disorder; stem cell biology; stem cell niche; stem cells; transcriptomics; translational study

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.

项目总结/摘要 该提案描述了一个为期5年的研究和职业发展计划，将使Jarish Cohen博士能够 实现他的长期目标，成为一个独立资助的医生，科学家研究如何调节T 干细胞（Tcells）在发育、稳态和疾病期间保护皮肤上皮干细胞。目前， 关于皮肤驻留免疫细胞用于保护皮肤上皮干细胞的机制知之甚少。 炎性皮肤病和脱发中的细胞。拟议的研究将集中在揭示 TGF1 α保护毛囊干细胞（HFSC）免受自身反应性T细胞攻击的机制。科恩博士 已经产生了Treg介导的HFSC免受自身免疫攻击的新的实验性体内模型， 非常类似于一种病态的人类疤痕性脱发此外，他还开创了一种高度 创新的局部技术，以删除基因，特别是在皮肤居民Teps，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，科恩博士将阐明 Treg介导的HFSC保护作用的时空动力学，并剖析皮肤Treg的作用机制 定位到HFSC利基。目的2将集中在阐明的不同机制，TdR在皮肤 和淋巴结用来保护HFSC免受破坏。在目标3中，科恩博士将利用 全面的转录组学和尖端的成像技术，以确定分子和途径， 人类瘢痕性脱发中Treg功能障碍和Treg定位模式改变汇总数据将 为我们理解THBE如何促进上皮干细胞的免疫耐受提供了重大进展 细胞，并有潜力确定新的治疗策略，以治疗人类皮肤病。 在加州大学旧金山弗朗西斯科（UCSF）从事博士后工作和担任临床讲师期间 科恩博士战略性地寻求额外的培训和指导， 皮肤免疫学在医学博士迈克尔·罗森布鲁姆的指导下，哲学博士、皮肤Treg专家 生物学，候选人，共同导师（博士杰森Cyster，博士，和Ophir Klein医学博士Ph.D.），和科学 顾问（Boris Bastian博士，医学博士，博士学位、和阿布·阿巴斯医学博士博士）已经发展了职业发展 计划科恩博士获得额外的经验，在国家的最先进的免疫学和尖端成像 技术，生物统计学，上皮干细胞生物学和科学交流。为了增强科恩医生 培训，由导师，科学顾问和Jayanta博士组成的多学科咨询委员会 Debnath，医学博士，加州大学旧金山分校病理学系主任，将每半年举行一次会议，审查他的进展， 支持他的职业发展。拟议的培训方案利用了 罗森布卢姆实验室，UCSF免疫学培训计划，以及UCSF皮肤科 和病理这将为科恩博士过渡到独立调查员提供一个理想的环境。