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.

项目概要/摘要该提案描述了一项为期 5 年的研究和职业发展计划，该计划将使贾里什·科恩 (Jarish Cohen) 博士能够实现他的长期目标，成为一名独立资助的医师科学家，研究监管 T 细胞（Treg）在发育、稳态和疾病过程中保护皮肤上皮干细胞。现在，关于皮肤驻留免疫细胞用于保护皮肤上皮干的机制知之甚少炎症性皮肤病和脱发中的细胞。拟议的研究将侧重于揭示 Tregs 保护毛囊干细胞 (HFSC) 免受自身反应性 T 细胞攻击的机制。科恩博士生成了一种新的体内实验模型，该模型可通过 Treg 介导保护 HFSC 免受自身免疫攻击，这与人类疤痕性脱发的高度病态非常相似。此外，他还开创了高度创新的局部技术，专门删除皮肤驻留性 Tregs 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。在目标 1 中，科恩博士将阐明 Treg介导的HFSC保护的时空动力学并剖析皮肤Treg的机制 HFSC 利基市场的本地化。目标 2 将重点阐明皮肤中 Tregs 的独特机制和淋巴结用于防止 HFSC 破坏。在目标 3 中，科恩博士将利用全面的转录组和尖端成像技术来识别分子和通路人类疤痕性脱发中 Treg 功能障碍和 Treg 定位模式改变。汇总数据将为我们理解Tregs如何促进上皮干细胞的免疫耐受性提供了重大进展细胞并有潜力确定治疗人类皮肤病的新治疗策略。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期间皮肤病理学服务中心，科恩博士战略性地寻求额外的培训和指导皮肤免疫学。在皮肤Treg专家Michael Rosenblum博士的指导下生物学、候选人、共同导师（Jason Cyster 博士和 Ophir Klein 医学博士、哲学博士）和科学顾问（Boris Bastian 医学博士、哲学博士和 Abul Abbas 医学博士、哲学博士）制定了职业发展计划计划让科恩博士获得最先进的免疫学和尖端成像方面的额外经验技术、生物统计学、上皮干细胞生物学和科学传播。为了增强科恩博士的培训，一个由导师、科学顾问和 Jayanta 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 Debnath 医学博士将每两年召开一次会议，回顾他的进展并支持他的职业发展。拟议的培训计划利用了以下机构的综合资源：罗森布鲁姆实验室、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。这将为科恩博士转变为独立调查员提供理想的环境。