Genetic and Environmental Determinants of Fertility: From Meiosis to Ovarian Aging

Sexual reproduction depends on the accurate formation of haploid gametes, sperm and eggs, through meiosis, a specialized cell division in which one round of genome replication is followed by two rounds of chromosome segregation. During this process, germ cells differentiate into highly specialized gametes. Mammalian gametogenesis shows marked sexual dimorphism: spermatogenesis is a continuous process throughout most adulthood, whereas oogenesis begins during fetal development when the size of the ovarian reserve is set. Once this reserve is depleted, ovarian function ceases, triggering menopause and associated health risks such as osteoporosis, cardiovascular disease, and metabolic disorders. Furthermore, errors during gametogenesis can cause other critical social issues like aneuploidy or infertility. The main goal of our research team is to uncover the molecular mechanisms that regulate gametogenesis and fertility in mammals, including humans, and to understand how these processes influence reproductive health and aging. By clarifying these pathways, we aim to identify the origins of critical societal challenges such as infertility, aneuploidy, and ovarian aging, and develop strategies to treat and prevent them. In this grant proposal, we will focus on three aspects that arise from our previous studies: Aim 1. To study the function of TRIP13 in meiotic prophase. TRIP13 is a master regulator of the meiotic cell cycle, controlling double-strand break (DSB) repair and chromosome axis formation among other processes. While TRIP13s role has been linked to remodeling HORMA domain proteins, our preliminary work suggests its ATPase activity is dispensable for some functions, indicating unexpected scaffolding roles. This proposal will use genetic, proteomic, genomic, and cell biology approaches to uncover these functions. Aim 2. To assess the impact of SARS-CoV-2 infection on spermatogenesis. Our preliminary data indicate that COVID-19 disrupts testicular architecture and impairs germ cell function. We will comprehensively analyze how SARS-CoV-2 infection affects meiotic progression and spermatogenesis, providing insights into its long-term consequences for male fertility and improving preparedness for future pandemics. Aim 3. To elucidate the genetic basis of ovarian aging and explore treatments to protect the follicle pool. We previously identified several genomic loci associated with the age of natural menopause. Building on this, we will investigate additional genetic determinants of ovarian reserve, focusing on functional analysis of folliculogenesis in mouse models. Furthermore, we will evaluate SKQ1, a mitochondria-targeted antioxidant that we showed it can prevent ovarian aging, as a novel pharmacological strategy to treat primary ovarian insufficiency. The successful completion of these objectives will significantly advance our understanding of meiosis, gametogenesis, and ovarian aging. These findings have the potential to inform new diagnostic tools and therapeutic strategies for infertility, aneuploidy, and reproductive aging, ultimately contributing to improved reproductive health and quality of life.