Defining the contributions of apoptosis to germline syncytium function during oogenesis

/Abstract The health of female gametes (oocytes) decreases exponentially as maternal age increases causing infertility and miscarriage risks. Infertility affects at least 1 in 4 women of childbearing age in North America and more worldwide. While medical interventions including in vitro fertilization (IVF) have improved reproductive success, this is strongly dependent on gamete health. In a human female, oocyte production (oogenesis) begins before birth where two-thirds of precursor oocytes are normally eliminated by programmed cell death (apoptosis). The few germline cells that escape apoptosis mature into oocytes. Apoptosis affects oocyte quality through unknown mechanisms. Studies on the contribution of apoptosis to maternal fertility are limited due to challenges with performing experiments on humans and even mice, and an underrepresentation of women's health studies in science. Identifying mechanisms that promote oocyte health will enhance our understanding of factors leading to infertility and aid fertility health research. Organ structure is tightly coupled to function, and the ovaries where oocytes are made are no exception. Throughout animal phylogeny, oogenic germlines are syncytial; they comprise of large, elaborate cells wherein many nuclei reside in connected compartments. My preliminary work with the oogenic germline of the model animal Caenorhabditis elegans revealed that disrupting germline structure prevented apoptosis and decreased fertility. How apoptosis removes certain precursor oocytes at the expense of others is unknown. The goal of this study is to determine the role of apoptosis in oogenesis and oocyte health as a conserved mechanism like apoptosis may explain ovary autonomous mechanisms in place to control oocyte quality before ovulation. The experiments proposed will be performed using the oogenic germline of C. elegans, due to similarities in proportional time scales of age-related oocyte quality decline and syncytial nature of precursor oocytes within the ovary. C. elegans has profound experimental advantages including a simple regulation of apoptosis. The proposed work will be conducted under the mentorship of Dr. Amy Shaub Maddox, with valued collaborators and a vibrant scientific community. Dr. Maddox has extensive experience with C. elegans, contractility, cell shape regulation, advanced imaging methods, and theoretical modeling. The lab is well-equipped with all the tools necessary to define the interplay between apoptosis in germline architecture and function. This project provides a comprehensive training opportunity for me by teaching me animal physiology and cell biology, microscopy and data analysis, and mathematical modeling. I will obtain professional development through mentoring undergraduates, attending networking events, writing, and publishing my work, and presenting at cell biology conferences like the Triangle Cytoskeleton and the American Society for Cell Biology meetings, with the ultimate goal of becoming an independent scientist faculty member at a research university in the US. Project Number: 1F32HD117621-01 | Fiscal Year: 2025 | NIH Institute/Center: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | Principal Investigator: Udodirim Onwubiko | Institution: UNIV OF NORTH CAROLINA CHAPEL HILL, CHAPEL HILL, NC | Award Amount: $75,520 | Activity Code: F32 | Study Section: Special Emphasis Panel[ZRG1 F06-J (20)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1F32HD11762101