An Organ-on-Chip Approach to Evaluation of Reproductive Health, Aging and Disease inWomen - Project Summary/Abstract: Uterine aging is a key factor in the age-related decline of women’s health and is associated with infertility, poor pregnancy outcomes and increased cancer risk. Spaceflight has been shown to rapidly induce symptoms that mimic aging in humans, as well as reproductive health in animals. Moreover, more and more female astronauts are experiencing long-duration tours in space with even longer durations are expected for Mars flight and future space endeavors. There is therefore a critical need to improve understanding of the mechanisms of uterine aging and the impacts of spaceflight on reproductive health. At the same time, there is a critical need to identify therapeutic approaches that can repair or protect against uterine aging. We therefore propose to adapt our microfluidic model of the endometrium to develop a µfluidic Human Uterus-on-chip to study Reproductive Aging (UHURA). For establishment of UHURA we propose to integrate uterine smooth muscle cells to our current endometrial model composed of endometrial epithelium, stroma, and endothelium and integrate complex hormone exposure protocols that mimic the menstrual cycle. Models will be established across multiple ethnicities and age ranges to identify population differences and improve understanding of the mechanisms of uterine aging. In the UG3 phase we will conduct extensive studies to validate model compatibility with spaceflight challenges, integrate with Redwire’s MVP spaceflight-worthy hardware, which is currently deployed at the International Space Station-National Laboratory (ISS-NL), and ensure UHURA is spaceflight ready. We will also conduct a 28-day or 56-day, one or two menstrual cycles, experiment in the MVP system at the ISS-NL. Effluent will be collected and properly stored, and chips fixed prior to return to support physiologic and multiomic analyses. Pathway models to support mechanistic characterization will be constructed from the multiomic data. We will also use our existing AI/ML network modeling techniques to identify drug targets and existing drugs to serve as potential candidates for therapeutic treatment of uterine aging. Finally, in the UH3 phase, we will elucidate the protective/anti-aging effects of known and newly identified candidate therapeutic compounds (quercetin and candidates from UG3). Dosing, safety, and administration route preclinical data will be collected on ground and a carefully planned efficacy experiments at the ISS-NL will be conducted. At the end of the UH3 phase, we will prepare for FDA presubmission.
