# The Aging Pituitary/Gonadal Axis

> **NIH NIH P01** · WICHITA STATE UNIVERSITY · 2024 · $2,137,513

## Abstract

Project Summary/Abstract - Overall
This integrated program project was pursuant to the discovery of naturally occurring, partially glycosylated
follicle-stimulating hormone (FSH) glycoforms by the Bousfield laboratory. Two of these glycoforms possessed 3
of 4 N-glycans, exhibited greater biological activity, and were more abundant than fully-glycosylated FSH in young
women. Furthermore, hypo-glycosylated FSH variants exhibited an age-dependent decrease concomitant with
a well-known decline in fertility in women. Projects are organized to reflect the recognition of the importance of
the development of numerous mouse genetic models in previous funding periods inspired by biochemical
advances in understanding of the FSH glycoforms, and which now, will inspire in turn, such studies at the
signaling, trafficking, and structural biology levels. In Project 1(Kumar), powerful genetic models now make it
possible to study each specific glycoform independently, both by injection of purified glycoform preparations into
Fshb-null mice as well as in transgenic mice expressing FSH18, FSH21, or FSH24. Advances in single-cell
RNA-sequencing coupled with a transgenic line that expresses green fluorescent protein specifically in
gonadotropes permit evaluation of the more than 50 enzymes responsible for N-linked oligosaccharide
synthesis. Since non-ovarian targets of FSH have raised concerns and confusion for women undergoing IVF,
several mouse models were devised to address questions raised by conflicting experimental outcomes,
beginning with deletion of the Fshr gene, which would effectively eliminate all forms of putative FSHR proteins,
including alternative splicing. In Project 2(Davis), studies involving FSH glycoform signals within primary cultures
of granulosa cells, focus on the disparate responses of ovarian target cells to biased agonists FSH18, FSH21, and
FSH24. Two major, differentially glycoform-regulated transcription factors (TF), CREB and YAP1, will have their
downstream pathways characterized in granulosa cells. Granulosa cells of young and advanced age mice and
women will provide basic information relevant to translational efforts. The interface between FSH and FSHR, both
monomeric and oligomeric receptor forms, will be studied in Project 3(Jonas). Activation of cAMP accumulation
is now known to involve FSHR dynamics that will be evaluated, including internalization. FSH glycoforms are
anticipated to alter FSHR conformation to varying degrees, leading to biased agonist signals. Project
4(Bousfield) will incorporate FSHR into lipid nanodiscs to provide a means to evaluate glycoform-FSHR-
membrane interactions, using cryogenic electron microscopy (cyro-EM). This has been done with LH and TSH
receptors (LHR & TSHR) and those studies have revealed the ligand binding site undergoes a major rotation,
lifting it away from the membrane, during receptor activation. The location of FSH oligosaccha-rides is on the
back side of the hormone, away from the hormo...

## Key facts

- **NIH application ID:** 10848221
- **Project number:** 5P01AG029531-12
- **Recipient organization:** WICHITA STATE UNIVERSITY
- **Principal Investigator:** GEORGE R BOUSFIELD
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $2,137,513
- **Award type:** 5
- **Project period:** 2009-04-15 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10848221

## Citation

> US National Institutes of Health, RePORTER application 10848221, The Aging Pituitary/Gonadal Axis (5P01AG029531-12). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10848221. Licensed CC0.

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