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

项目摘要/摘要 据估计，10%的美国人患有自身免疫性疾病，而绝大多数受影响的人 女人。本申请为医生提出了一个五年的有指导的职业发展和研究计划。 科学家将在皮肤免疫学领域建立一个利基市场，专注于系统性等自身免疫性疾病 红斑狼疮对女性的影响不成比例。通过研究导致人类死亡的生物机制 对于这种性别偏见，候选人试图找到新的方法来治疗并潜在地防止这些毁灭性的 疾病。这位候选人在整个培训过程中都表现出了对研究的承诺，并准备好参加 在学术医学方面的职业。这一奖项将促进实现她长期职业目标所需的培训： (1)确立独立研究员和皮肤科学术领先者的地位，并有自己的事业 专注于皮肤免疫学，(2)建立资助研究的方案线，以改进 了解女性偏向自身免疫的皮肤免疫学并寻找新的治疗靶点 (3)学会提供专门的指导，以促进各级受训人员的职业发展。 职业发展计划：通过正式课程、授课研讨会和导师的实践培训 和他们的实验室人员，候选人将获得所需的科学和职业发展培训，以实现 这些目标。她建议在系统生物学应用、老鼠建模等方面获得特定的科学技能 研究复杂的人类疾病，以及研究皮肤和系统免疫学的方法。同时， 她将追求她的职业发展目标，即融入科学界，增强领导力 和指导技能，并获得翻译研究道德行为的实践技能。 工作环境：应聘者是密歇根大学皮肤科的临床讲师 约翰·古德琼森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 包括狼疮和人类疾病的老鼠模型的国际专家。她有足够的机会接触到州政府- 最先进的设施和设备，来自其他内科科学家导师的动手培训和指导，以及 皮肤科对职业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，同时 确定偏向女性的因子VGLL3如何导致女性皮肤中的自身免疫性疾病。目标1将 明确VGLL3如何与转录因子相互作用，通过整合人类细胞培养促进自身免疫 用系统生物学的方法进行转基因小鼠的研究。AIM 2将使用蛋白质组学数据和验证 用siRNA介导的基因敲除方法确定影响皮肤细胞VGLL3活性的因素 有狼疮和无狼疮的男女都有。AIM 3将确定VGLL3在驾驶过程中如何与癌基因YAP结合 并在狼疮患者皮肤细胞和狼疮样疾病小鼠身上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.