LHCGR signaling and responses during ovarian aging

About This Grant

Significance to VA: According to the Centers for Disease Control and Prevention, female infertility is a major health problem and affects about 6-10% percent (~7.5 million) of women at the reproductive age in the United States. The infertility rates for women Veterans is greater than the general population and is also greater than age-matched active duty women. This translates to well over 100,000 female Veterans. The issue of infertility in Veterans is recognized by the recently introduced Veterans Infertility Treatment Act of 2023 (HR 544) requiring VA to furnish infertility care to veterans and their partners. Ovarian senescence begins about age 30 and over the next 10 to 15 years is manifest by infertility and decreased steroid output. Although ovarian aging is a natural physiological process, cessation of ovarian function at midlife increases susceptibility to the development of co- morbidities, such as osteoporosis, which decrease quality of life and increases healthcare burden. There is currently no intervention for infertility or preventing/delaying the cessation of ovarian function, thus, highlighting an unmet need for novel approaches to tackle this problem. Innovation and impact: Innovation lies in the use of aging ovary models: granulosa cells recovered from young and older reproductive aged women and mice. Innovation lies in the context of understanding the actions of hCG in the aging ovary. Innovation is also derived from our ability to obtain and analyze granulosa cells from patients that have good or poor responses to IVF stimulation, which would facilitate patient phenotyping and personalized treatment plans. Innovation lies in the application of state-of-the-art multi-omics approaches, RNA-seq, CUT&RUN, and ATAC-seq, on matched samples to identify differential binding patterns of selected transcription factors and to profile chromatin accessibility between young and advanced reproductive aged women in response to hCG. The approach will identify and test new candidate genes as potential targets to improve fertility. Specific aims: (1) Determine the transcriptional programs in granulosa cells of young and advanced reproductive age mice and women. We hypothesize that key transcriptional regulators (YAP1 and TAZ) are differentially regulated during aging. We also hypothesize that genomic occupation of YAP1 and TAZ is altered in granulosa of patients who are good responders and poor responders to ovarian stimulation for IVF. (2) Identify and determine the role of hCG-responsive, YAP- and TAZ-target genes in granulosa cells of young and advanced reproductive age mice and women. We will test the hypothesis that YAP1-specific and TAZ- specific target genes will have distinct roles in modulating granulosa cell function. Furthermore, we propose that hCG-mediated, TAZ-responsive genes will improve the health and differentiation of aging granulosa cells, whereas hCG-mediated, YAP1-responsive genes will promote proliferation. Methodology: This project makes use of in vivo aging mouse models using granulosa cells recovered from young and older reproductive age women and mice. We will employ multi-omics (CUT&RUN, ATAC-seq, and RNA-seq) on the same samples to determine and validate specific gene targets to improve the diagnosis and treatment of infertility in women. Path to translation/implementation: This study impacts the VA-ORD Translational Pipeline (TP) Stages T0-1, Disease Biology / pathology (Foundational Studies), T0-2, Target Identification, Evaluation & Efficacy (Proof-of-Concept Studies) and T0-3B, Validation of biomarkers in different populations. We anticipate discovering unique differences in the actions of hCG in granulosa cells as a function of age and patient IVF response. This research will identify and validate new targets, which will facilitate patient phenotyping based on patient age and response. Next steps are to employ in vivo preclinical models using small molecule inhibitors to demonstrate efficacy for improvement of ovarian function and fertility.