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.

Grant Number: 5K08AR078251-05
NIH Institute/Center: NIH
Principal Investigator: Allison Billi