Mechanisms of immune regulation in the skin

描述（由申请人提供）：本提案描述了一个为期5年的培训计划，用于发展皮肤免疫学领域的学术生涯。该候选人毕业于威斯康星州医学院的医学科学家培训项目（MSTP）。他的研究生工作主要集中在免疫耐受的基本机制上，在完成博士学位后，候选人将他的第三和第四年医学院与皮肤免疫调节的博士后研究项目相结合。他最近毕业于加州大学旧金山分校的皮肤科住院医师，在那里他接受了分子医学医生-科学家培训途径的培训。在他的居住期间，在过去的一年里，作为UCSF的初级教员，候选人建立了一个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，候选人将扩大他的科学技能，并成为研究皮肤基本免疫学的独立调查员。他将通过课程，参加研讨会和会议，国家演讲，并在指导研究项目的参与来实现这一目标。 Abul Abbas博士将指导候选人的科学发展。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。为了加强候选人的培训，一个由德高望重的资深科学家组成的咨询委员会将提供科学和职业建议。咨询委员会将包括 免疫学家（Mark安德森博士，医学博士，哲学博士，加州大学旧金山分校医学和内分泌学助理教授）、皮肤生物学家（加州大学旧金山分校皮肤学教授Thea Mauro博士）和皮肤遗传学家（郭佩仁博士，医学博士，博士，皮肤病学教授，UCSF）。 研究将侧重于揭示皮肤免疫调节的基本机制。目前，人们对外周组织中的免疫反应是如何控制的知之甚少。使用一种新的CD 4 + T细胞介导的炎症小鼠模型，该研究项目将剖析负责减弱皮肤中这些反应的机制。这项工作将集中在调节性T细胞和PD-1/PD-L1通路上。此外，差异基因表达分析将用于揭示T细胞介导和角质形成细胞介导的免疫调节的新机制。该项目将把在小鼠中获得的结果转化为患有炎症性皮肤病的人类。这些汇总数据将为我们理解T细胞介导的免疫反应如何在皮肤中调节提供重大进展，并有可能为炎症性皮肤病的新型治疗方法奠定基础。 拟议的培训计划借鉴了阿巴斯实验室，UCSF免疫学计划和UCSF皮肤科的综合资源。这将为候选人过渡到独立调查员提供理想的环境。 公共卫生相关性：慢性炎症性皮肤病，如牛皮癣和湿疹性皮肤病与大量的发病率和显著降低的健康相关的生活质量。这些疾病给患者带来的心理和经济负担是巨大的。该提案中概述的研究旨在增强我们对这些疾病的理解，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.