Molecular understanding of maternal humoral responses to pregnancy

PROJECT SUMMARY Complications from preterm birth are the leading causes of global mortality in children under the age of five. The failure to mount appropriately-timed maternal-fetal immune tolerance is associated with preterm delivery. However, our current understanding of the humoral immune system in this process has been limited to a handful of examples of pathogenic antibodies that occur with pregnancy complications in humans. To fill this knowledge gap, it is essential to obtain a comprehensive portrait of autoimmune repertoire dynamics during normal and complicated pregnancies. The long-term goal of this work is to leverage serological autoantibody profiles for development of non-invasive predictors for preterm delivery and identification of key targets for preventative immunomodulatory therapeutics. In Aim 1, Dr. Rackaityte will chronicle the autoimmune changes across the time course of pregnancy using phage display immunoprecipitation and sequencing to generate machine learning models predictive of gestational age. Completed during the K99 phase, this high-resolution timeline of autoreactivity during pregnancy will build the foundation for understanding the roles, both protective and pathogenic, of these critical humoral immune adaptations. In Aim 2, Dr. Rackaityte will dissect antibody- antigen interactions specific to preterm pregnancy to discover contact points that lead to functional inhibition of the targeted protein. In the K99 phase, a suite of patient-informed recombinant antibodies will be generated through an evolution-driven antibody phage display system, and these will be tested in the R00 phase for their ability to inhibit target protein function. This will provide the framework for future studies to interfere with antibody-antigen interactions to prevent preterm delivery. In Aim 3, Dr. Rackaityte will develop murine models of inflammation during pregnancy that will be employed to determine the in vivo consequences of maternal autoantibodies on pregnancy outcome. This will deliver a validated model for interrogating the in vivo role of autoantibodies that lead to labor progression, a unique opportunity to mechanistically dissect observations made in humans for targeted therapeutic development. Dr. Rackaityte’s goal is to develop an independent research program in translational reproductive immunology, which is highly complementary to the mission of UCSF geared towards facilitating direct interactions between basic scientists and clinicians. To accomplish her goals, Dr. Rackaitye will receive guidance from her scientific advisory committee and her primary mentor, Dr. Joseph DeRisi. To complete her training and build a foundation of skills for her independent laboratory, she will develop expertise in recombinant antibody generation (with Dr. Charles Craik), mouse model development (with Drs. Tippi MacKenzie and Mark Anderson), and clinical metadata analysis of reproductive disorders (with Dr. Marcelle Cedars). She will attend UCSF and MOSAIC UE5 sponsored programs to gain skills in grant writing, leadership, and lab management as well as targeted coursework to prepare her successful transition to an independent career.