Elucidating mechanisms of tolerance to commensal skin bacteria

 描述(由申请者提供)：本提案描述了一项为期5年的学术生涯发展培训计划，重点是研究皮肤细菌的适应性免疫反应，以及炎症性皮肤病的临床重点。Scharschmidt博士在加州大学旧金山分校(UCSF)获得医学博士学位和论文。作为一名医学生和霍华德·休斯医学研究所-NIH研究学者，她的研究生工作重点是微丝蛋白在皮肤屏障功能、过敏反应易感性和皮肤微生物群中的作用。这让她做好了独特的准备，可以检查皮肤屏障上的宿主和微生物之间的相互作用。她最近从加州大学旧金山分校的皮肤科住院医师毕业，在那里她被NIH支持的T32项目医生-科学家培训计划录取，该计划结合了临床培训和博士后研究奖学金。在她的博士后工作期间，以及过去一年在加州大学旧金山分校皮肤科担任初级教员期间，沙尔施密特博士战略性地寻求皮肤免疫学和微生物学方面的额外培训和指导。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、研究道德指导、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。沙尔施密特博士的目标是成为一名独立的研究员，研究建立和维持对皮肤共生细菌的免疫耐受性的机制。她将通过课程作业、参加研讨会和会议、国家报告和参与有指导的研究项目来实现这一目标。目前，人们对免疫耐受的机制知之甚少，这种机制允许皮肤淋巴细胞持续感知共生细菌的抗原，而不会引发破坏性炎症。这项拟议的研究将集中于揭示这些细胞和分子耐受机制，这些机制对于保持皮肤动态平衡至关重要，当它们被打破时，会导致炎症性皮肤病。沙尔施密特博士利用她开发的研究皮肤细菌抗原特异性反应的创新模型，进行了一项新颖的观察，即新生儿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被激活的调节性T细胞(Treg)群体，它们在出生第一周后以惊人的突然波动进入皮肤。在拟议的实验中，Scharschmidt博士将阐明这些新生儿皮肤Tregs在建立对皮肤共生的耐受性方面的功能作用，并剖析导致它们在新生儿皮肤中戏剧性积累的机制。她还致力于建立和验证人源化的小鼠模型，以研究人类皮肤对共生细菌的适应性免疫反应。这些汇总的数据将为我们理解T细胞介导的对共生细菌的免疫反应是如何调节的提供重大进展，并有可能为炎症性皮肤病的新治疗方法奠定基础。沙尔施密特博士将受益于一种联合导师模式，这种模式利用了一名资深教员的经验，以及两名非常有前途的初级教员的资源和科学专业知识。阿布·阿巴斯博士将是指导沙尔施密特博士科学和事业发展的资深导师。阿巴斯博士是加州大学旧金山分校的教授和病理学系主任，也是免疫耐受领域的世界知名领导者。他在指导博士后研究员和研究生方面的记录非常出色。这项研究将在迈克尔·罗森布鲁姆博士的实验室进行，他是皮肤科助理教授，曾是阿巴斯博士的实习生。罗森布鲁姆博士将提供拟议工作所需的资源和空间，并就免疫耐受的特定皮肤方面提供指导。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，在微生物-宿主相互作用方面提供科学专业知识，并就Scharschmidt博士的职业发展提供这方面的导师。阿巴斯博士仍然与罗森布鲁姆实验室保持密切联系，并参加每周一次的实验室会议，为他们提供持续的指导。为了加强Scharschmidt博士的培训，一个由三位共同导师、资深内科科学家兼皮肤生物学家Theodora Mauro博士和加州大学旧金山分校皮肤科主任Bruce Wintroub博士组成的咨询委员会将每年召开两次会议，回顾她的进步并支持她的职业发展。拟议的培训计划利用了罗森布鲁姆实验室、加州大学旧金山分校免疫学培训计划、加州大学旧金山分校微生物致病和宿主防御培训计划以及加州大学旧金山分校皮肤科的综合资源。这将为沙尔施密特博士向独立研究人员的转变提供理想的环境

 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