Wednesday, May 8, 2024
5/8/2024
PROJECT SUMMARY Ovulation is essential for human fertility. During ovulation, a fluid filled antral cavity that forms late in folliculogenesis expands and, in coordination with thinning of a distinct region of the follicle wall, leads to rupture and release of the cumulus oocyte complex. Impaired ovulation resulting from endocrinopathies, ovarian pathologies, idiopathic anovulation, or ovarian aging are associated with decreased fertility. Improving our understanding of ovulation biology will contribute to the development of novel treatment strategies for infertility, as well as development of new non-hormonal contraceptives that block follicle rupture during ovulation. Although previous research has elucidated many of the molecular mechanisms that underlie ovulation, less attention has been paid to the role of biomechanical forces within the ovarian follicle in driving follicle rupture. Prior research has characterized an increase in pressure in the region of the ovulatory follicle within the ovary; however, this work was unable to distinguish the role of follicle-intrinsic forces from the external forces from the surrounding ovarian microenvironment. Our lab and others have demonstrated formation of the antrum in an ex vivo model of folliculogenesis and ovulation, suggesting that follicle-intrinsic forces drive fluid flow and cavity expansion in the ovulatory follicle. Therefore, we will apply our ex vivo model of ovulation to study the follicle-intrinsic biomechanical forces that drive ovulation, a promising strategy to integrate new technologies into the study of ovulation and address unanswered questions about the role that pressure, wall tension, and fluid accumulation plays in ovulation. Our overarching hypothesis is that increased intrafollicular pressure exerts disproportionate wall tension on the rupturing side of the follicle due to localized wall thinning and that the intrafollicular pressure increase is driven in part by downregulation of TRPV4 leading to reduced calcium efflux and increased fluid influx into the antrum. We will quantify intrafollicular pressure and regional wall tension within ovulatory follicles to determine if excess wall tension in one region of the follicle is predictive of the site of rupture. We will also examine the role of TRPV4 as a novel regulator of antral cavity expansion and subsequent ovulation efficacy. The long-term goal of the proposed work is to elucidate fundamental aspects of ovulation biology and to pioneer the use of novel technologies that can quantify biomechanical parameters of follicle rupture to study conditions of anovulatory infertility and to develop novel non-hormonal contraceptive agents, all of which align directly with my own long-term career goals. Ultimately, the translational nature of this project, the rich intellectual infrastructure of the Northwestern Center for Reproductive Science, and my interdisciplinary mentoring team spanning disciplines of biomechanics, mathematics, bioinformatics, and reproductive science and medicine will provide me with support and unprecedented skill sets to develop into an independent clinician-scientist.
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