Grant: Discovery Grants Program - Individual

Ovarian fibrosis is characterized by excessive deposition of extracellular matrix, leading to tissue stiffness and functional dysregulation. This age-related condition has been identified as an underlying mechanism for reduced fertility and ovarian dysfunction. Notably, anti-fibrotic drug treatments have restored fertility in aged mice. Our recent work showed that metformin has protective effect against age-related ovarian fibrosis through modulation of fibroblasts and macrophages. Additionally, we observed an earlier onset of fibrosis in immunocompromised mice. In that study, we discovered ligands secreted by macrophages exclusive to the metformin group and their corresponding fibroblast receptors, whose functions remain to be determined. This implies a crucial role for immune cells in maintaining ovarian integrity and support our hypothesis that the loss of immune cell with age is a key player in ovarian fibrosis. Nonetheless, we propose that cumulative ovulations and wound repair over a reproductive lifetime act as chronic stressors paired to the loss of macrophage functions that contribute to age-related ovarian fibrosis. The overarching goal of our research program is to deepen our understanding of normal age-associated ovarian fibrosis, essential for improving both human fertility and livestock reproductive performance. Our short-term objectives for the next five years are threefold: Aim 1: We will investigate the role of ovulation frequency in the development of age-associated ovarian fibrosis using mouse models with varying rates of ovulation. Ovarian tissues will undergo histological assessments and single-cell sequencing. Aim 2: We will evaluate the role of macrophages in the onset of ovarian fibrosis using various immunocompromised mouse models with specific immune cells defects. Our aim is to discern how the absence of specific immune cells and variations in ovulation frequency influence ovarian fibrosis, which will be assessed through histological analysis. Aim 3: We will characterize the molecular pathways in normal mouse ovarian fibroblasts, focusing on the newly identified ligand-receptor affecting fibroblast activation and remodelling functions. Employing a multidisciplinary approach, our research aims to fill gaps in the fundamental understanding of reproductive biology, particularly concerning ovarian fibrosis. This study will provide the first evidence that ovulation frequency is indeed a risk factor for ovarian fibrosis and will elucidate both the biological processes and the immune contributions to that risk. These findings could inform targeted interventions to extend fertility, thereby prolonging the productive lifespan of both humans and production animals, such as dairy cows, contributing to a more sustainable and ethical approach to animal husbandry.