The project aims to investigate the role of the cGAS-STING pathway and cellular senescence in ovarian aging, with a focus on developing treatments to prevent ovarian reserve loss.
Ovarian aging is a complex process, ultimately culminating in menopause, which marks the cessation of fertility in women. This process is influenced by various factors, including age, genetics, lifestyle, health conditions, medical interventions, and body weight. Beyond infertility, menopause brings forth a range of additional health concerns, including decreased bone density and an elevated risk of cardiovascular disease, leading to a reduced period of good health (healthspan) for postmenopausal women compared to men. Chronic inflammation poses a significant threat to our well-being, standing as one of the widely acknowledged "Hallmarks of Aging" that delineate the primary factors contributing to bodily decline. Strikingly, inflammation within the ovaries is a dangerous but often underestimated phenomenon. It serves as a catalyst for Diminished Ovarian Reserve (DOR), which not only results in female infertility but can also result in early menopause.
The project aims to explore the potential of cGAS-STING pathway inhibition as a target to treat ovarian aging. This general objective will be achieved through the realization of four specific objectives (workpackages, WP): - WP1. Identification of the specific cells associated with the cGAS-STING pathway activation in aging, and validation of cGAS-STING pathway activation as a target for early DOR in human samples. This WP will help us to determine the translational effect of our findings for designing the future clinical trial after our experimental approach with the new drugs. The observation and corroboration of our experimental data in humans will allow us to show targets in the population that can be treated in clinical trials with the new molecules. - WP2. Validation of cGAS-STING pathway activation as a target for chemotherapy-induced DOR. - WP3. Development and in vitro evaluation of the pharmacological efficacy of novel cGAS-STING pathway inhibitors. - WP4. Evaluation of the efficacy of cGAS-STING pathway inhibition in animal models of age-induced and chemotherapy-induced DOR.
The first milestone (1 year after the start of the project) will include the work described in WP1, WP2, and half of WP3 (see Project Description), being the deliverables the following: • Validation of cGAS/STING as a target for DOR, which would include: • Data showing significant protection against chemotherapy or age-induced DOR in STING KO mouse. • Data showing significant involvement of the cGAS-STING pathway in age-induced DOR and/or chemotherapy-induced DOR in human patients. • Plan for in vivo testing based on patient data. • At least one novel synthesized inhibitor based on docking studies against STING
The second milestone will include the work described in the second half of WP3, and WP4 (see Project Description).