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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：
9753932
负责人：
Tiffany Crawford Scharschmidt
金额：
$ 18.04万
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/9753932
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 Data Data Aggregation Dermatology Development Disease Doctor of Medicine Engineering Ethics Faculty Fellowship Foundations Goals Hair follicle structure Health Promotion Homeostasis Host Defense Human Immune Tolerance Immune system Immunodeficient Mouse Immunology Individual Infection Inflammation Inflammatory Institutes Knowledge Laboratories Life Ligands Lymphocyte MHC Class II Genes Mediating Medical Medical Students Mentors Mentorship Microbiology Modeling Molecular Morbidity - disease rate Neonatal Pathogenesis Pathology Patient Care Physicians Play Population Postdoctoral Fellow Predisposition Prevalence Production Program Development Psoriasis Regulatory T-Lymphocyte Research Research Personnel Research Project Grants Residencies Resources Role San Francisco Science Scientist Skin Skin colonization Staphylococcus epidermidis Statistical Data Interpretation T cell response T-Lymphocyte Testing Therapeutic Time Training Training Programs Translating United States National Institutes of Health Universities Wild Type Mouse Work adaptive immune response allergic response antigen-specific T cells career career development cell mediated immune response chemokine chronic inflammatory skin clinical care commensal bacteria commensal microbes cytokine experience experimental study filaggrin graduate student health related quality of life host-microbe interactions human disease humanized mouse in vivo in vivo Model innovation insight lymph nodes meetings member microbial microbial colonization microbiome mouse model neonatal period novel novel therapeutic intervention novel therapeutics preservation professor programs public health relevance recruit response senior faculty skills skin barrier skin disorder skin microbiome 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（由申请人提供）：该提案描述了一个为期5年的培训计划，用于发展学术生涯，研究重点是对皮肤细菌的适应性免疫反应和炎症性皮肤病的临床重点。沙夏博士获得了医学博士学位。与论文从加州大学，旧金山弗朗西斯科（UCSF）。她作为医学生和霍华德休斯医学研究所-NIH研究学者的研究生工作集中在丝聚蛋白在皮肤屏障功能，过敏反应易感性和皮肤微生物组中的作用。这为她研究皮肤屏障处的宿主-微生物相互作用做了独特的准备。她最近毕业于加州大学旧金山分校的皮肤科住院医师，在那里她被接受进入医生科学家培训计划，NIH支持的T32计划结合临床培训与博士后研究奖学金。在她的博士后工作，并在过去的一年中，作为一个初级教员在加州大学旧金山分校的皮肤科，博士Scharschloves战略性地寻求额外的培训和指导在皮肤免疫学和微生物学。通过拟议的培训计划，她将扩大她在这些领域的专业知识，并获得对专业发展，研究道德行为，统计分析和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员，研究建立和维持对皮肤共生细菌的免疫耐受性的机制。她将通过课程，参加研讨会和会议，国家演示和参与指导研究项目来实现这一目标。目前，对免疫耐受的机制知之甚少，免疫耐受允许皮肤淋巴细胞持续感知来自肠道细菌的抗原而不引发破坏性炎症。拟议的研究将侧重于揭示这些细胞和分子耐受机制，这些机制对保持皮肤稳态至关重要，当被打破时，会导致炎症性皮肤病。使用她开发的用于研究对皮肤细菌的抗原特异性反应的创新模型，Scharschloss博士进行了新的观察，即新生儿期是建立对皮肤细菌耐受性的关键窗口。她还发现了一个独特而丰富的活化调节性T细胞（Tcells）群体，它们在生命的第一周后以一种非常突然的波进入皮肤。在拟议的实验中，Scharschleman博士将阐明这些新生儿皮肤TdR在建立对皮肤过敏的耐受性方面的功能作用，并剖析其在新生儿皮肤中急剧积累的机制。她还旨在建立和验证一种人源化小鼠模型，以研究人类皮肤对细菌的适应性免疫反应。这些汇总数据将为我们理解T细胞介导的免疫反应如何调节提供重大进展，并有可能为炎症性皮肤病的新型治疗方法奠定基础。Scharschalder博士将受益于一种共同导师模式，该模式借鉴了一位高级教师的经验，以及两名非常有前途的初级教师的资源和科学专业知识。Abul Abbas博士将担任高级导师，指导Scharschalmer博士的科学和职业发展。Abbas博士是UCSF病理学系的教授和主席，也是免疫耐受领域的世界知名领导者。他指导博士后研究员和研究生的记录是杰出的。这项研究将在皮肤科助理教授Michael Rosenblum博士的实验室进行，他曾是Abbas博士的实习生。Rosenblum博士将为拟议的工作提供所需的资源和空间，并就免疫耐受的皮肤特异性方面提供指导。生物工程和治疗科学助理教授Michael Fischbach博士将担任第三位共同导师，提供微生物与宿主相互作用的科学专业知识，并在Scharschlett博士的职业发展方面提供指导。Abbas博士仍然与Rosenblum实验室保持密切联系，并参加每周的实验室会议，提供连续的指导。为了加强Scharschlett博士的培训，一个由所有三位共同导师以及高级医学科学家和皮肤生物学家Theodora Mauro博士和UCSF皮肤科主任布鲁斯温特劳布博士组成的咨询委员会将每年举行两次会议，以审查她的进展并支持她的职业发展。拟议的培训计划借鉴了Rosenblum实验室，UCSF免疫学培训计划，UCSF微生物发病机制和宿主防御培训计划以及UCSF皮肤科的综合资源。这将为Scharschloss博士转变为独立调查员提供一个理想的环境