Mechanisms of sex discrepancy in autoimmune disease: Regulation of the female-biased VGLL3 immune pathway

项目总结/摘要 据估计，10%的美国人患有自身免疫性疾病，绝大多数受影响的人是 妇女本申请提出了一个为期五年的指导职业发展和研究计划的医生 科学家在皮肤免疫学领域建立了一个利基，专注于自身免疫性疾病，如系统性 红斑狼疮对女性的影响尤为严重。通过研究导致 对于这种性别偏见，候选人寻求找到新的途径来治疗和潜在地预防这些破坏性的疾病。 疾病候选人在整个培训过程中表现出对研究的承诺，并准备 学术医学的职业生涯。该奖项将促进实现其长期职业目标所需的培训： (1)建立自己作为一个独立的调查员和国家领导人在学术皮肤病学，与职业生涯 （2）建立一个资助研究的项目线，以提高 了解皮肤免疫学，并确定新的治疗目标，在女性偏见的自身免疫性 疾病，以及（3）学会提供专门的指导，以促进各级学员的职业发展。 职业发展计划：通过正式课程、教学研讨会和导师的实践培训 及其实验室人员，候选人将获得实现所需的科学和职业发展培训， 这些目标。她建议获得系统生物学应用，小鼠建模， 复杂的人类疾病，以及皮肤和全身免疫学的研究方法。与此同时， 她将追求她的职业发展目标，与科学界融合，提高领导能力， 和指导技能，并获得实践技能的转化研究的道德行为。 环境：候选人是密歇根大学皮肤科的临床讲师。 Johann Gudjonsson博士的免疫学实验室。她计划通过这笔赠款扩大她的导师圈子 包括狼疮和人类疾病小鼠模型的国际专家。她有足够的机会进入国家- 最先进的设施和设备，实践培训和其他医生科学家导师的指导，以及 皮肤科对职业发展和实验室发展的大力支持。 研究设计：提出的科学目标将促进候选人的职业发展目标， 确定女性偏好因子VGLL 3如何驱动女性皮肤中的自身免疫性疾病。AIM 1将 定义VGLL 3如何与转录因子相互作用，通过整合人细胞培养物来促进自身免疫 以及用系统生物学方法进行转基因小鼠研究。AIM 2将使用蛋白质组学数据和验证 通过siRNA介导的敲低来鉴定来自以下患者的人皮肤细胞中控制VGLL 3活性的因子： 无论男女都有狼疮AIM 3将确定VGLL 3如何与癌基因雅普相互作用， 在狼疮患者皮肤细胞和患有狼疮样疾病的小鼠中测试一种潜在的治疗方法。

PROJECT SUMMARY/ABSTRACT An estimated 10% of Americans suffer from autoimmune disease, and the vast majority of those affected are women. This application proposes a five-year mentored career development and research plan for a physician scientist to establish a niche in the field of skin immunology focused on autoimmune diseases such as systemic lupus erythematosus that disproportionately affect women. By investigating the biological mechanisms that lead to this sex bias, the candidate seeks to find new avenues to treat and potentially prevent these devastating diseases. The candidate has demonstrated commitment to research throughout her training and is poised for a career in academic medicine. This award will facilitate the training required to achieve her long-term career goals: (1) Establish herself as an independent investigator and national leader in academic dermatology, with a career focused on cutaneous immunology, (2) Establish a programmatic line of funded research to improve understanding of cutaneous immunology and identify new therapeutic targets in female-biased autoimmune disease, and (3) Learn to provide dedicated mentorship to foster career development of trainees at all levels. Career development plan: Through formal coursework, didactic seminars, and hands-on training from mentors and their lab personnel, the candidate will attain the scientific and career development training needed to achieve these goals. She proposes to acquire specific scientific skills in systems biology applications, mouse modeling of complex human disease, and approaches for study of cutaneous and systemic immunology. Simultaneously, she will pursue her career development goals of integrating with the scientific community, enhancing leadership and mentoring skills, and acquiring practical skills for the ethical conduct of translational research. Environment: The candidate is a clinical lecturer at the University of Michigan working in the cutaneous immunology laboratory of Dr. Johann Gudjonsson. She plans to expand her mentorship circle through this grant to include international experts on lupus and mouse models of human disease. She has ample access to state- of-the-art facilities and equipment, hands-on training and guidance from other physician scientist mentors, and strong support for career and laboratory development from the Department of Dermatology. Research design: The proposed scientific aims will foster the candidate's career development goals while determining how the female-biased factor VGLL3 drives autoimmune disease in the skin of women. AIM 1 will define how VGLL3 interacts with transcription factors to promote autoimmunity by integrating human cell culture and transgenic mouse studies with a systems biology approach. AIM 2 will use proteomics data and validation by siRNA-mediated knockdown to identify factors governing VGLL3 activity in human skin cells from patients of both sexes with and without lupus. AIM 3 will determine how VGLL3 interfaces with the oncogene YAP in driving autoimmunity and test a potential therapy in lupus patient skin cells and mice with lupus-like disease.