Elucidating mechanisms of tolerance to commensal skin bacteria

阐明对共生皮肤细菌的耐受机制

基本信息

批准号：
8947751
负责人：
Tiffany Crawford Scharschmidt
金额：
$ 13万
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：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8947751
关键词：
Adult Advisory Committees Antigens Area Atopic Dermatitis Automobile Driving Bacteria Biological Assay Biomedical Engineering CCL8 gene CCR8 gene CD4 Positive T Lymphocytes California Cell surface Chairperson Chronic Clinical Complex Cutaneous Cytokine Activation Data Data Aggregation Dermatology Development Disease Doctor of Medicine Engineering Ethics Faculty Fellowship Foundations Goals Hair follicle structure Health Homeostasis Host Defense Human Immune Tolerance Immune system Immunodeficient Mouse Immunology Individual Infection Inflammation Inflammatory Institutes Institutional National Research Service Award Knowledge Laboratories Life Ligands Lymphocyte MHC Class II Genes Mediating Medical Medical Students Mentors Mentorship Microbe Microbiology Modeling Molecular Morbidity - disease rate Neonatal Pathogenesis Pathology Patients Physicians Play Population Postdoctoral Fellow Predisposition Prevalence Production Program Development Psoriasis Regulatory T-Lymphocyte Relative (related person)Research Research Personnel Research Project Grants Residencies Resources Role San Francisco Science Scientist Skin Staphylococcus epidermidis T cell response T-Lymphocyte Testing Therapeutic Time Training Training Programs Translating United States National Institutes of Health Universities Wild Type Mouse Work adaptive immunity allergic response career career development cell mediated immune response chemokine clinical care commensal microbes experience filaggrin graduate student health related quality of life human disease in vivo in vivo Model innovation insight lymph nodes meetings member microbial microbial colonization microbiome mouse model novel novel therapeutic intervention novel therapeutics professor research study response skills skin disorder stem symposium

项目摘要

DESCRIPTION (provided by applicant): This proposal describes a 5-year training program for the development of an academic career with a research focus in the adaptive immune response to skin bacteria and a clinical focus in inflammatory skin disease. Dr. Scharschmidt obtained an M.D. with thesis from the University of California, San Francisco (UCSF). Her graduate work as a medical student and Howard Hughes Medical Institute-NIH Research scholar focused on the role of filaggrin in skin barrier function, predisposition to allergic responses and the skin microbiome. This has uniquely prepared her to examine host-microbe interactions at the skin barrier. She recently graduated from a dermatology residency at UCSF where she was accepted into in the Physician-Scientist Training Program, an NIH supported T32 program combining clinical training with a post-doctoral research fellowship. During her post-doctoral work and over the past year as a junior faculty member in UCSF's department of dermatology, Dr. Scharschmidt has strategically sought out additional training and mentorship in both cutaneous immunology and microbiology. Through the proposed training program, she will expand upon her expertise in these areas as well as gain skills critical for professional development, ethical conduct of research, statistical analysis, and clinical care of patients with inflammatory skin disease. Dr. Scharschmidt's goal is to become an independent investigator studying the mechanisms responsible for establishing and maintaining immune tolerance to skin commensal bacteria. She will accomplish this through coursework, participation in seminars and conferences, national presentations and engagement in a mentored research project. Currently, little is known about the mechanisms of immune tolerance that allow skin lymphocytes to continuously sense antigens from commensal bacteria without eliciting destructive inflammation. The proposed research will focus on uncovering these cellular and molecular tolerance mechanisms, which are critical to preserving skin homeostasis and which, when broken, contribute to inflammatory skin disease. Using an innovative model that she developed to study the antigen-specific response to skin bacteria, Dr. Scharschmidt has made the novel observation that the neonatal period is a critical window for establishing tolerance to skin commensal bacteria. She has also discovered a unique and abundant population of activated regulatory T cells (Tregs) that enter the skin after the first week of life in a remarkably abrupt wave. In the proposed experiments, Dr. Scharschmidt will elucidate the functional role of these neonatal skin Tregs in establishing tolerance to skin commensals and dissect mechanisms responsible for their dramatic accumulation in neonatal skin. She also aims to establish and validate a humanized mouse model to study the adaptive immune response to commensal bacteria in human skin. The aggregate data will provide a major advancement in our understanding of how T cell-mediated immune responses to commensal bacteria are regulated and have the potential to establish a foundation for novel therapeutic approaches for inflammatory skin disease. Dr. Scharschmidt will benefit from a co-mentorship model that draws on the experience of a senior faculty member as well as the resources and scientific expertise of two highly promising junior faculty. Dr. Abul Abbas will be the senior mentor guiding Dr. Scharschmidt's scientific and career development. Dr. Abbas is Professor and Chairman of the Department of Pathology at UCSF and a world-renowned leader in the field of immune tolerance. His 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 tolerance. Dr. Michael Fischbach, an Assistant Professor of Bioengineering and Therapeutic Sciences will serve as the third co- mentor, providing scientific expertise on microbe-host interactions and mentorship on this aspect of Dr. Scharschmidt's career development. Dr. Abbas remains closely tied to the Rosenblum lab and participates in weekly lab meetings, providing continuity of mentorship. To enhance Dr. Scharschmidt's training, an advisory committee consisting of all three co-mentors as well as Dr. Theodora Mauro, a senior physician-scientist and cutaneous biologist, and Dr. Bruce Wintroub, chair of the UCSF dermatology department, will meet twice yearly to review her progress and support her career development. The proposed training program draws on the combined resources of the Rosenblum Laboratory, the UCSF Immunology Training Program, The UCSF Microbial Pathogenesis and Host Defense Training Program and the UCSF Department of Dermatology. This will provide an ideal setting for Dr. Scharschmidt's transition to an independent investigator

描述（应用程序提供）：该提案描述了一项为期5年的学术职业培训计划，研究重点是对皮肤细菌的适应性免疫响应，并在炎症性皮肤病中临床重点。 Scharschmidt博士获得了加利福尼亚大学旧金山大学（UCSF）的论文。她作为医学生的研究生工作和霍华德·休斯医学院（Howard Hughes Nih Institute）研究学校的重点是Filaggrin在皮肤屏障功能中的作用，对过敏反应和皮肤微生物组的倾向。这已经使她唯一地准备了皮肤屏障处的宿主 - 微叶片相互作用。她最近毕业于UCSF的皮肤科住所，在那里她被接受参加医师科学家培训计划，NIH支持T32计划，该计划将临床培训与博士后研究奖学金相结合。 Scharschmidt博士在加州大学UCSF皮肤病学系的初级教职员工中，在过去的一年中以及过去一年中担任初级教职员工期间，Scharschmidt博士在策略性地占据了皮肤免疫学和微生物学方面的额外培训和心态。通过拟议的培训计划，她将扩大自己在这些领域的专业知识，并获得对专业发展，研究，统计分析的道德行为以及炎症性皮肤病患者的临床护理至关重要的技能。 Scharschmidt博士的目标是成为一名独立研究者，研究负责建立和维持对皮肤共生细菌免疫耐受性的机制。她将通过课程，参加半决赛，国家演讲以及参与研究项目的参与来实现这一目标。当前，对免疫耐受性的机制知之甚少，这些机制使皮肤淋巴细胞继续在不引起破坏性感染的情况下继续感知共生细菌的抗原。拟议的研究将着重于发现这些细胞和分子耐受性机制，这些机制对于保存皮肤稳态至关重要，并且在破裂时会导致炎症性皮肤病。 Scharschmidt博士利用她开发的创新模型来研究对皮肤细菌的抗原特异性反应，使新生儿时期是建立对皮肤共生细菌耐受性的关键窗口。她还发现了一个独特而丰富的活性调节T细胞（TREG），这些细胞（Tregs）在生命的第一周后在突然突然的波浪中进入皮肤。在拟议的实验中，Scharschmidt博士将阐明这些新生皮肤Tregs在建立对皮肤分子的耐受性和剖析其在新生儿皮肤中急剧积累的机制中的功能作用。她还旨在建立和验证人源化的小鼠模型，以研究人类皮肤中共生细菌的适应性免疫响应。骨料数据将为我们了解如何调节T细胞介导的对共生细菌的免疫回应的理解提供了重大进步，并有可能为炎症性皮肤疾病的新型治疗方法建立基础。 Scharschmidt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两个高度有前途的初级教师的资源和科学专业知识。 Abul Abbas博士将是指导Scharschmidt博士的科学和职业发展的高级导师。 Abbas博士是UCSF病理学系教授兼董事长，也是免疫耐受性领域的世界知名领导者。他心理的博士后研究员和研究生的记录非常出色。这项研究将在迈克尔·罗森布鲁姆（Michael Rosenblum）博士的实验室进行，他是皮肤病学系的助理教授，也是阿巴斯博士的前学员。 Rosenblum博士将提供提议的工作所需的资源和空间，以及有关免疫耐受性特定于皮肤方面的指导。生物工程和治疗科学助理教授迈克尔·费斯巴赫（Michael Fischbach）博士将担任第三位同事，在Scharschmidt博士的职业发展方面提供有关微生物互动和心态的科学专业知识。 Abbas博士与Rosenblum实验室密切相关，并参加每周实验室会议，提供心态的连续性。为了增强Scharschmidt博士的培训，由所有三位副主管组成的咨询委员会以及高级身体科学家和皮肤生物学家Theodora Mauro博士以及UCSF Dermotology Department主席Bruce Wintroub博士将每年一次见面两次，以审查她的进步并支持她的职业发展和支持她的职业发展。拟议的培训计划借鉴了Rosenblum实验室，UCSF免疫学培训计划，UCSF微生物发病机理和宿主防御培训计划以及UCSF皮肤病学的组合资源。这将为Scharschmidt博士向独立调查员的过渡提供理想的环境