Studying the Function of TRIP13 in Meiotic Prophase
We aim to dissect the multifaceted role of TRIP13, a conserved AAA+ ATPase critical cell cycle regulator. We and others have shown that it is involved in double-strand break (DSB) repair, chromosome axis formation, desynapsis, meiotic silencing of unsynapsed chromatin (MSUC), and the spindle assembly checkpoint (Roig et al., 2010; Pacheco et al., 2015; Marcet-Ortega et al., 2017; Marcet-Ortega et al, MS in preparation). Most of these functions have been linked to the ability of this protein to use the energy of the hydrolysis of an ATP molecule to remodel HORMA domain-containing proteins (e.g., MAD2, HORMAD1, or REV7). Nonetheless, our unpublished
findings suggest that the ATPase function of TRIP13 might be dispensable for specific meiotic roles, like DSB repair. These data indicate that TRIP13 may have potential scaffolding functions, something that has not been previously described in any other model organism. To reveal this, we have created an ATPase-dead conditional mutant mouse model, allowing us to express the ATPase-dead TRIP13 protein specifically in meiocytes. We aim to uncover these scaffolding functions using genetic, proteomic, genomic, and cell biology tools. This research will advance our understanding of TRIP13’s function in meiosis and hold potential implications for cancer research since TRIP13 has been implicated in several types of solid tumors, opening avenues for collaboration with other groups.
Investigating the Long-Term Effects of SARS-CoV-2 Infection on Testicular Function
Our lab has identified that fatal SARS-CoV-2 infection can cause significant damage to the germ cells, particularly to undifferentiated spermatogonia, the stem cell population that provides germ cells to sustain male fertility during adulthood (Martinez-Marchal and López-Panadés, et al., submitted). Interestingly, we also observed spermatogonia stem cell loss in patients who have recovered from COVID-19. These findings suggest that the infection with SARS-CoV-2 can cause
permanent damage to the testis, limiting their ability to produce sperm in the long term. Over the next few years, we will explore the long-term effects of this loss, the susceptibility mechanisms of spermatogonia to SARS-CoV-2, and potential treatments to mitigate this damage. This research is crucial for understanding the reproductive consequences of COVID-19 and developing strategies to protect male fertility in the context of viral infections.
Uncovering Genetic Determinants of the Ovarian Reserve
Building on our well-established collaboration with the labs of Dr. John Perry (University of Cambridge, UK), Dr. Anna Murray (University of Exeter, UK), and Dr. Eva Hoffmann (University of Copenhagen, Denmark), which led to the identification of 290 genomic loci associated with the age of natural menopause (Ruth, Day, Hussain, Martínez-Marchal, et al., 2021), we aim to identify additional genetic factors that influence the ovarian reserve. To achieve this, we will leverage exome and whole genome sequencing data from over 150,000 women in the UK Biobank to associate genetic variations with the age of natural menopause. Subsequently, we will conduct
functional analyses using mouse models to elucidate the effects of these genetic variants on ovarian aging. Currently, we are focusing on the functional analysis of two genes, Secisbp2 and Bend2, identified through these analyses. These investigations will explore their roles in folliculogenesis and the establishment and maintenance of the ovarian reserve.
Developing Protective Treatments for the Follicular Reserve
We will continue our develop novel treatments to delay ovarian aging. Based on the
genomic loci associated with the age of natural menopause, we hypothesized that treatment with the mitochondria-targeted antioxidant SkQ1 could protect the ovarian reserve from the effects of aging. Our in vivo tests in mice have shown promising results, positioning SkQ1 as a potential candidate for the first pharmacological treatment to delay menopause onset in women. In the coming years, we will further evaluate SkQ1’s impact on fertility across different ages and strains of mice.
We will also design novel molecules based on SkQ1 to enhance our intellectual property strategy and advance toward bringing this technology to the market.