Endometriosis autoantibody target discovery and functional validation.

PROJECT SUMMARY/ABSTRACT Endometriosis is a disorder of ectopic endometrium-like tissue that affects 10% of reproductive-age people with a uterus. Despite its prevalence, it is difficult to diagnose, taking an average of 4-11 years for definitive diagnosis, and has a high rate of recurrence after hormonal and surgical therapies. The humoral immune response in endometriosis has the potential to shed insight into disease pathophysiology and diagnostic biomarkers. However, our understanding of the role antibodies play in endometriosis is largely limited to the knowledge that up to 50% of patients have anti-endometrial autoantibodies, and that a subset of infertility patients with endometriosis have autoantibodies against laminin-111 that contribute to early miscarriage. In addition, there is evidence that altered extracellular matrix (ECM) protein expression and remodeling plays a pathogenic role in endometriosis. Preliminary data suggest that patients with endometriosis have an enrichment of autoantibodies that target the ECM compared to patients with other uterine disorders. The long-term goal of this work is to identify autoantibodies that are specific to endometriosis that will serve as non-invasive diagnostics, and to examine the functional impact of ECM-targeting autoantibodies. This will be accomplished in Aim 1 by characterizing the specific reactivity of autoantibodies to ECM proteins expressed in endometriotic lesions and interrogating their functional consequences in cellular invasion assays using endometriotic spheroids. In Aim 2, unbiased serological antibody profiling and machine learning will be leveraged to identify a minimal set of endometriosis-associated autoantibody targets. This will provide a concrete list of biomarkers that can be leveraged as a non-surgical diagnostic and will be validated using an independent cohort. These experiments will accelerate the development of methods to definitively diagnose, prevent, and ultimately treat endometriosis. Under this fellowship, the applicant will be supported by extraordinary clinical and research training in the University of California San Francisco’s MD/PhD program. A mentorship team consisting of experts in the reproductive sciences, immunology, and computational methods will support the applicant in achieving her goal of becoming a physician-scientist gynecologist who studies the intersection of reproductive health disorders and dysregulated immunity.