Dissecting the Role of Regulatory T cells in Epidermal Stem Cell Differentiation

剖析调节性 T 细胞在表皮干细胞分化中的作用

• 批准号: 9224916
• 负责人: Anubhav Narain Mathur
• 金额: $ 18.9万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-17 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9224916
• 关键词: Ablation; Advisory Committees; Allergic inflammation; Alpha Cell; Area; Arthritis; Atopic Dermatitis; Biological Assay; Biological Models; Biology; CD4 Positive T Lymphocytes; CXCR4 gene; Cell Cycle Kinetics; Cell Differentiation process; Cell Lineage; Cell physiology; Cells; Chairperson; Childhood; Chronic; Clinical; Cutaneous; Cytokine Network Pathway; Cytokine Receptors; Data; Data Aggregation; Defect; Dermatologic; Dermatology; Development; Disease; Doctor of Medicine; Doctor of Philosophy; Epidermis; Epithelial; Ethics; Exhibits; FOXP3 gene; Faculty; Fellowship; Foundations; Functional disorder; Goals; Hair follicle structure; Homeostasis; Human; Immune; Immune Tolerance; Immune response; Immune system; Immunology; Indiana; Inflammation; Inflammatory; Inflammatory Infiltrate; Injury; Interleukin-10; Interleukin-17; Intestines; Kinetics; Label; Laboratories; Link; Lung; Mediating; Medicine; Mentors; Mentorship; Modeling; Molecular; Multiple Sclerosis; Mus; Natural regeneration; Pathogenesis; Pathology; Pathway interactions; Patients; Physicians; Play; Population; Postdoctoral Fellow; Process; Program Development; Proliferating; Psoriasis; Quantitative Reverse Transcriptase PCR; Recovery; Recruitment Activity; Regulatory T-Lymphocyte; Research; Research Personnel; Research Project Grants; Residencies; Resources; Role; Scientist; Skin; Skin injury; Statistical Data Interpretation; Stem Cell Research; Stem cells; Testing; Time; Tissues; Training; Training Programs; Transcriptional Regulation; Trauma; United States National Institutes of Health; Universities; Water; Work; adult stem cell; career; career development; chemokine receptor; chronic inflammatory skin; clinical care; cytokine; epidermis cell; experience; experimental study; graduate student; immunoregulation; innovation; insight; keratinocyte; keratinocyte differentiation; medical schools; member; mouse model; novel; novel therapeutics; pathogen; pediatric patients; professor; programs; regenerative; repaired; response; senior faculty; skills; skin barrier; skin disorder; stem; stem cell biology; stem cell differentiation; stem cell niche; symposium; transcription factor; Ablation; Advisory Committees; Allergic inflammation; Alpha Cell; Area; Arthritis; Atopic Dermatitis; Biological Assay; Biological Models; Biology; CD4 Positive T Lymphocytes; CXCR4 gene; Cell Cycle Kinetics; Cell Differentiation process; Cell Lineage; Cell physiology; Cells; Chairperson; Childhood; Chronic; Clinical; Cutaneous; Cytokine Network Pathway; Cytokine Receptors; Data; Data Aggregation; Defect; Dermatologic; Dermatology; Development; Disease; Doctor of Medicine; Doctor of Philosophy; Epidermis; Epithelial; Ethics; Exhibits; FOXP3 gene; Faculty; Fellowship; Foundations; Functional disorder; Goals; Hair follicle structure; Homeostasis; Human; Immune; Immune Tolerance; Immune response; Immune system; Immunology; Indiana; Inflammation; Inflammatory; Inflammatory Infiltrate; Injury; Interleukin-10; Interleukin-17; Intestines; Kinetics; Label; Laboratories; Link; Lung; Mediating; Medicine; Mentors; Mentorship; Modeling; Molecular; Multiple Sclerosis; Mus; Natural regeneration; Pathogenesis; Pathology; Pathway interactions; Patients; Physicians; Play; Population; Postdoctoral Fellow; Process; Program Development; Proliferating; Psoriasis; Quantitative Reverse Transcriptase PCR; Recovery; Recruitment Activity; Regulatory T-Lymphocyte; Research; Research Personnel; Research Project Grants; Residencies; Resources; Role; Scientist; Skin; Skin injury; Statistical Data Interpretation; Stem Cell Research; Stem cells; Testing; Time; Tissues; Training; Training Programs; Transcriptional Regulation; Trauma; United States National Institutes of Health; Universities; Water; Work; adult stem cell; career; career development; chemokine receptor; chronic inflammatory skin; clinical care; cytokine; epidermis cell; experience; experimental study; graduate student; immunoregulation; innovation; insight; keratinocyte; keratinocyte differentiation; medical schools; member; mouse model; novel; novel therapeutics; pathogen; pediatric patients; professor; programs; regenerative; repaired; response; senior faculty; skills; skin barrier; skin disorder; stem; stem cell biology; stem cell differentiation; stem cell niche; symposium; transcription factor

Project Summary/Abstract This proposal describes a 5-year training program for the development of an academic career with a research focus on immune regulatory mechanisms that govern epidermal stem cell differentiation in inflammatory skin disease. Dr. Mathur obtained an M.D. and Ph.D. from Indiana University School of Medicine's MSTP program. His graduate work focused on the transcriptional regulation (including roles for Stat3, Stat4, and T-bet) of IL- 17-secreting CD4+ T cells (Th17 cells). These cells have now been implicated in the pathogenesis of numerous inflammatory diseases including psoriasis, arthritis, and multiple sclerosis. This along with his clinical training in dermatology and fellowship training in pediatric dermatology has uniquely prepared him to examine how skin-resident regulatory T cells function to influence stem/progenitor cell differentiation and epidermal regeneration in inflammatory skin disease. Dr. Mathur recently graduated from a dermatology residency at Indiana University. Thereafter, he was recruited to UCSF's Physician-Scientist Training Program, an NIH supported T32 program combining clinical training in Pediatric Dermatology with a post-doctoral research fellowship. During his post-doctoral work and over the past year as a junior faculty member in UCSF's Department of Dermatology, Dr. Mathur has strategically sought out additional training and mentorship in cutaneous immunology, skin barrier function and epidermal stem cell biology. Through the proposed training program, he will expand upon his expertise in these areas as well as gain skills critical for professional development, ethical conduct of research, statistical analysis, and clinical care of pediatric patients with inflammatory skin disease. Dr. Mathur's goal is to become an independent investigator studying the mechanisms responsible for establishing and maintaining immune homeostasis in the skin. He will accomplish this through coursework, participation in seminars and conferences, national presentations and engagement in a mentored research project. Currently, little is known about how skin-resident immune cells influence epidermal stem cell function in inflammatory skin diseases. Nevertheless, stem/progenitor cell activation is necessary to repair skin barrier defects following inflammatory insults. The proposed research will focus on uncovering the cellular and molecular mechanisms by which regulatory T cells (Treg) support stem cell activation and epidermal regeneration. Dr. Mathur has made the novel observation that skin Tregs are abundant and co-localize with a population of epidermal stem cells that reside within the hair follicle bulge (HFSCs). Furthermore, Tregs influence HFSC activation, which supports keratinocyte differentiation and skin barrier repair after inflammatory skin injury. In the proposed experiments, Dr. Mathur will elucidate how skin-Tregs promote epidermal regeneration. Using sophisticated mouse model systems, he will dissect how regulatory T cells control epidermal cell differentiation both at the cellular and molecular levels. The aggregate data will provide a major advancement in our understanding of how Tregs promote epidermal barrier homeostasis, and have the potential to establish a foundation for novel therapeutic strategies for inflammatory skin disease. Dr. Mathur will benefit from a co-mentorship model that draws on the experience of senior faculty members as well as the resources and scientific expertise of a promising junior faculty member. Drs. Richard Locksley M.D. and Abul Abbas M.D. will be the senior mentors guiding Dr. Mathur's scientific and career development. Dr. Locksley is an HHMI investigator, Professor of Medicine at UCSF, and a preeminent scientist whose laboratory focuses on allergic inflammation in barrier tissues including skin, lung and intestines. Dr. Abbas is Professor and Chairman of the Department of Pathology at UCSF and a world-renowned leader in the field of immune tolerance. Their combined record of mentoring postdoctoral fellows and graduate students is outstanding. The research will be conducted in the laboratory of Dr. Michael Rosenblum, who is an Assistant Professor in the Department of Dermatology and a former trainee of Dr. Abbas. Dr. Rosenblum will provide the resources and space required for the proposed work as well as guidance on skin-specific aspects of immune regulation. To enhance Dr. Mathur's training, a scientific advisory committee consisting of all three co-mentors as well as Dr. Theodora Mauro, a senior physician-scientist and cutaneous biologist who has expertise in keratinocyte biology and barrier function, Dr. Ophir Klein M.D., Ph.D., a physician-scientist with expertise in adult stem cell and regenerative biology, and Dr. Bruce Wintroub, chair of the UCSF dermatology department, will meet twice yearly 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, The UCSF Center of Regeneration Medicine and Stem Cell Research, and the UCSF Department of Dermatology. This will provide an ideal setting for Dr. Mathur's transition to an independent investigator.

项目摘要/摘要 该提案描述了一项为期5年的培训计划，以研究学术生涯的发展 专注于控制炎症皮肤表皮干细胞分化的免疫调节机制 疾病。 Mathur博士获得了医学博士学位和博士学位。来自印第安纳大学医学院的MSTP计划。 他的研究生工作着重于IL-的转录法规（包括STAT3，STAT4和T-BET的角色） 17分泌CD4+ T细胞（Th17细胞）。这些细胞现已与 许多炎症性疾病，包括牛皮癣，关节炎和多发性硬化症。这与他的 皮肤病学和小儿皮肤病学研究金培训的临床培训使他唯一准备 检查皮肤居民调节性T细胞如何影响茎/祖细胞分化和 炎症皮肤病的表皮再生。 Mathur博士最近毕业于印第安纳大学的皮肤科住院医师。此后，他是 NIH支持了UCSF的医师科学家培训计划，该计划支持临床的T32计划 通过博士后研究奖学金培训小儿皮肤病学。在他的博士后工作中 在过去的一年中，是UCSF皮肤病学系的初级教职员工，Mathur博士 从战略上寻求皮肤免疫学，皮肤屏障功能和 表皮干细胞生物学。通过拟议的培训计划，他将扩大自己在这些方面的专业知识 领域以及提高技能对于专业发展至关重要，伦理学研究，统计 分析和对炎性皮肤疾病的小儿患者的临床护理。 Mathur博士的目标是成为 一个独立的研究人员，研究了负责建立和维持免疫的机制 皮肤稳态。他将通过课程工作，参加研讨会和 会议，国家演讲和参与指导的研究项目。 目前，关于皮肤居住的免疫细胞如何影响表皮干细胞功能的知之甚少 炎症性皮肤疾病。然而，茎/祖细胞细胞激活对于修复皮肤屏障是必要的 炎症侮辱后的缺陷。拟议的研究将着重于发现细胞和 调节T细胞（TREG）支持干细胞激活和表皮的分子机制 再生。 Mathur博士已经使皮肤很丰富并与A共定位了新颖的观察结果 位于毛囊凸起（HFSC）内的表皮干细胞的种群。此外，Tregs 影响HFSC激活，该激活支持角质形成细胞分化和炎症后的皮肤屏障修复 皮肤损伤。在拟议的实验中，Mathur博士将阐明皮肤如何促进表皮 再生。使用复杂的小鼠模型系统，他将剖析调节性T细胞如何控制 表皮细胞分化在细胞和分子水平上。汇总数据将提供主要的 我们对Tregs如何促进表皮障碍稳态的理解的进步，并具有 为炎症性皮肤疾病的新型治疗策略建立基础的潜力。 Mathur博士将受益于一个会议模型，该模型借鉴了高级教师的经验 以及有前途的初级教师的资源和科学专业知识。博士。理查德·洛克斯利医学博士 Abul Abbas M.D.将是指导Mathur博士的科学和职业发展的高级导师。博士 洛克斯利（Locksley）是HHMI的研究员，UCSF医学教授，也是一位杰出的科学家 着重于皮肤，肺和肠道在内的屏障组织中的过敏性炎症。阿巴斯博士是教授 以及UCSF病理学系主席，以及免疫领域的世界知名领导人 宽容。他们指导博士后研究员和研究生的总记录非常出色。这 研究将在迈克尔·罗森布鲁姆（Michael Rosenblum）博士的实验室进行。 皮肤病学系和阿巴斯博士的前学员。 Rosenblum博士将提供资源和 拟议的工作所需的空间以及有关免疫调节的皮肤特定方面的指导。到 增强了Mathur博士的培训，该培训是一个科学咨询委员会，由所有三个副主管和博士组成 西奥多拉·毛罗（Theodora Mauro）是一位高级医师科学家和皮肤生物学家，在角质形成细胞中具有专业知识 生物学和障碍功能，Ophir Klein M.D. 再生生物学以及UCSF皮肤科主席Bruce Wintroub博士将见面两次 每年审查他的进步并支持他的职业发展。 拟议的培训计划借鉴了Rosenblum实验室的联合资源，UCSF 免疫学培训计划，UCSF再生医学和干细胞研究中心，以及 UCSF皮肤科系。这将为Mathur博士过渡到一个 独立研究者。