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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要/摘要该建议描述了一项为期5年的研究和职业发展计划，该计划将使Jarish Cohen博士能够实现他成为独立资助的医师科学家的长期目标，以研究监管细胞（Tregs）在发育，稳态和疾病期间保护皮肤上皮干细胞。现在，关于皮肤居住的免疫细胞用于保护皮肤皮上皮茎的机制知之甚少炎症性皮肤和脱发的细胞。拟议的研究将着重于发现 Tregs保护毛囊干细胞（HFSC）免受自动反应性T细胞攻击的机制。科恩博士已经产生了一种新型的Treg介导的HFSC保护免受自身免疫性攻击保护的实验性实验模型，这非常类似于人类疤痕性脱发的高度病态形式。此外，他还率先创新的局部技术以删除专门在居住的Treg中的基因，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AIM 1中，Cohen博士将阐明 Treg介导的HFSC保护的空间和时间动力学，并剖析皮肤的机理本地化HFSC利基市场。 AIM 2将集中于阐明皮肤中treg的不同机制和淋巴结用于保护HFSC破坏。在AIM 3中，Cohen博士将利用全面的转录组和尖端成像技术，以识别分子和途径 Treg功能障碍和在人疤痕性脱氧核对中的Treg定位模式改变。聚合数据将在我们对Treg如何促进上皮茎的免疫耐受性方面的理解方面提供了重大进步细胞并有可能识别治疗人皮肤病的新型治疗策略。在博士后工作期间，并在加利福尼亚大学旧金山大学（UCSF）担任临床讲师皮肤病理学服务，科恩博士在战略上寻求了其他培训和指导皮肤免疫学。在迈克尔·罗森布鲁姆（Michael Rosenblum，M.D.）博士的指导下，皮肤专家 Biology，候选人，联席会员（Jason Cyster博士，博士学位和Ophir Klein，M.D.，Ph.D。）和Scientific 顾问（医学博士Boris Bastian博士和Abul Abbas M.D.，Ph.D.）已开发了职业发展计划Cohen博士在最先进的免疫学和尖端成像方面获得额外的经验技术，生物统计学，上皮干细胞生物学和科学交流。增强科恩博士的培训是一个由导师，科学顾问和Jayanta博士组成的多学科咨询委员会 UCSF病理学系主席Debnath，医学博士，每两年见面，以审查他的进度和支持他的职业发展。拟议的培训计划借鉴了 Rosenblum实验室，UCSF免疫学培训计划和UCSF皮肤病学部门和病理。这将为科恩博士向独立研究者的过渡提供理想的环境。