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

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.