The requirement and function of metabolic activity in cumulus cells during late stages of ovulation.

About This Grant

PROJECT SUMMARY Bidirectional communication between the oocyte and its companion somatic cells is essential for oogenesis. Cumulus cells (CCs) are specialized cells that directly surround the oocyte within the antral follicle and provide nutrient and metabolic support. For example, due to the oocyte’s poor glycolytic capabilities, CCs can metabolize glucose and supply pyruvate which is then utilized by the oocyte through the tricarboxylic acid (TCA) cycle to fuel growth. The CCs are metabolically coupled to the oocyte through transzonal projections (TZPs), cytoplasmic extensions of the CCs that traverse the zona pellucida (ZP) of the oocyte and make connections via gap junctions. However, part way through ovulation (6 hr post-ovulation induction in the mouse), TZPs retract and CCs become metabolically uncoupled from the oocyte. Interestingly, however, I made the observation that CC metabolic pathways are actually upregulated around 8 hr post-ovulation induction, a timepoint after metabolic uncoupling from the oocyte occurs. Thus, my premise is that this increase in metabolism is essential to support intrinsic functions of the CCs which contribute to ovulation. In fact, during late stages of ovulation, cumulus cells are known to exhibit energetically demanding processes and behaviors that likely facilitate follicular rupture, including production and maintenance of a hyaluronan-rich extracellular matrix (ECM) and increased migration and invasion. The Duncan laboratory has previously demonstrated that ovulation and the integrity of the CC ECM is impaired with advanced reproductive age. Interestingly, the expression of metabolic pathways within CCs is reduced in COCs from reproductively old mice at 8 hr post-ovulation induction compared to young counterparts. Therefore, my overarching hypothesis is that increased metabolic activity of cumulus cells after metabolic uncoupling from the oocyte is required to support the intrinsic functions of the cumulus cells and is impaired with age. In Aim 1, I will define how regulation of CC metabolic activity correlates with TZP retraction and oocyte meiotic progression through transcriptional and functional assays. In Aim 2, I will determine if CC metabolism in late ovulation (8-12h post-ovulation induction) is essential for maintenance of the ECM and migratory and invasive behavior of CCs. Finally, in Aim 3, I will investigate how temporal regulation of CC metabolism across ovulation is affected by advanced reproductive age and how this may impact ECM integrity and CC behavior. This proposal will advance our knowledge of the role of CC metabolism in ovulation beyond their well characterized support of the oocyte in early stages of ovulation, and will further efforts to elucidate mechanisms underlying age-related impairments in ovulation. The comprehensive intellectual infrastructure of Northwestern’s Center for Reproductive Science and my interdisciplinary mentoring team spanning bioinformatics, metabolism, ovarian aging, and reproductive biology will provide me with the skillsets to become an independent researcher ready to apply my reproductive science knowledge to species conservation efforts.