Mechanisms of immune regulation in the skin

描述(由申请人提供)：本建议书描述了一项为期5年的培训计划，旨在发展皮肤免疫学领域的学术生涯。这位候选人毕业于威斯康星医学院的医学科学家培训计划(MSTP)。他的研究生工作重点是免疫耐受的基本机制，在完成博士工作后，这位候选人将他在医学院的第三和第四年与一个关于皮肤免疫调节的博士后研究项目结合在一起。他最近从加州大学旧金山分校的皮肤病住院医师培训毕业，在那里他接受了分子医学医生-科学家培训途径的培训。在他的住院期间，以及在过去的一年里，作为加州大学旧金山分校的初级教员，这位候选人建立了一种新的小鼠模型来研究皮肤中T细胞介导的免疫反应。通过拟议的培训计划，候选人将扩展他的科学技能，并成为研究皮肤基础免疫学的独立研究员。他将通过课程作业、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点。阿布·阿巴斯博士将指导候选人的科学发展。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。为了加强候选人的培训，一个由备受尊敬的资深科学家组成的咨询委员会将提供科学和职业建议。咨询委员会将由以下成员组成 一名免疫学家(加州大学旧金山分校医学和内分泌学助理教授Mark Anderson博士，博士)、一名皮肤生物学家(加州大学旧金山分校皮肤科教授Thea Mauro MD博士)和一名皮肤遗传学家(加州大学旧金山分校皮肤科教授郭培仁博士)。研究的重点将是揭示皮肤免疫调节的基本机制。目前，对外周组织中的免疫反应是如何控制的知之甚少。利用一种新的CD4+T细胞介导的炎症小鼠模型，该研究项目将剖析导致皮肤中这些反应减弱的机制。这项工作将集中在调节性T细胞和PD-1/PD-L1途径上。此外，差异基因表达分析将被用来揭示T细胞和角质形成细胞介导的免疫调节的新机制。该项目将把在小鼠身上获得的结果转化为患有炎症性皮肤病的人类。这些汇总的数据将为我们理解T细胞介导的免疫反应在皮肤中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。拟议的培训计划利用了阿巴斯实验室、加州大学旧金山分校免疫学项目和加州大学旧金山分校皮肤科的综合资源。这将为候选人向独立调查员的过渡提供理想的环境。 公共卫生相关性：慢性炎症性皮肤病，如牛皮癣和湿疹皮肤病，与大量的发病率和与健康相关的生活质量显著降低有关。这些疾病给患者带来的心理和经济负担是沉重的。这项提案中概述的研究旨在增进我们对这些疾病的了解，并为新的治疗策略提供基础。

DESCRIPTION (provided by applicant): This proposal describes a 5-year training program for the development of an academic career in the field of cutaneous immunology. The candidate graduated from the Medical Scientist Training Program (MSTP) at the Medical College of Wisconsin. His graduate work focused on basic mechanisms of immune tolerance, and upon completion of his doctoral work, the candidate combined his 3rd and 4th years of medical school with a post-doctoral research project on immune regulation in the skin. He recently graduated from a dermatology residency at UCSF where he trained in the Molecular Medicine Physician-Scientist Training Pathway. During his residency, and over the past year as a UCSF junior faculty member, the candidate established a novel mouse model to study T cell-mediated immune responses in the skin. Through the proposed training program, the candidate will expand upon his scientific skills and become and independent investigator studying the basic immunology of the skin. He will accomplish this through coursework, participation in seminars and conferences, national presentations, and engagement in a mentored research project. Dr. Abul Abbas will mentor the candidate's scientific 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. To enhance the candidate's training, an advisory committee of highly-regarded senior scientists will provide scientific and career advice. The advisory committee will consist of an immunologist (Dr. Mark Anderson, MD, PhD., Assistant Professor,of Medicine and Endocrinology at UCSF) a cutaneous biologist (Dr. Thea Mauro MD, Professor of Dermatology, UCSF), and a cutaneous geneticist (Dr. Pui-Yan Kwok MD, PhD., Professor of Dermatology, UCSF). Research will focus on uncovering basic mechanisms of immune regulation in the skin. Currently, little is known about how immune responses are controlled in peripheral tissues. Using a novel mouse model of CD4+ T cell-mediated inflammation, the research project will dissect the mechanisms responsible for attenuating these reactions in the skin. The work will focus on regulatory T cells and the PD-1/PD-L1 pathway. In addition, differential gene expression analysis will be utilized to uncover novel mechanisms of both T cell- mediated and keratinocyte-mediated immune regulation. The project will translate results obtained in mice to humans with inflammatory skin disease. The aggregate data will provide a major advancement in our understanding of how T cell-mediated immune responses are regulated in the skin, and have the potential to establish a foundation for novel therapeutic approaches for inflammatory skin disease. The proposed training program draws on the combined resources of the Abbas Laboratory, the UCSF Immunology Program, and the UCSF Department of Dermatology. This will provide an ideal setting for the candidate's transition to an independent investigator. PUBLIC HEALTH RELEVANCE: Chronic inflammatory skin diseases such as psoriasis and the eczematous dermatoses are associated with a significant amount of morbidity and markedly reduced health-related quality of life. The psychological and economic burden of these diseases on patients is profound. The research outlined in this proposal aims to enhance our understanding of these diseases and provide a foundation for novel therapeutic strategies.