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Using basic science and clinical research to define the molecular basis of vaginal epithelial dysfunction that negatively impacts reproductive health after menopause

Award Number: R56AG099541
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/15/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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Using basic science and clinical research to define the molecular basis of vaginal epithelial dysfunction that negatively impacts reproductive health after menopause - ABSTRACT Dysregulation of vaginal epithelial health in postmenopausal (PM) women is poorly defined. Half of PM women are affected by genitourinary syndrome of menopause (GSM), but this condition is also underdiagnosed and undertreated. It is known GSM is caused by loss of estrogen (E) production and its symptoms include vaginal dryness and dyspareunia. Topical E alleviates GSM, but its use dropped after a 2002 report linked hormonal replacement therapy to increased risk of breast cancer and cardiovascular disease. Though more recent data indicates these risks were overstated, topical E is now used by < 5% of U.S. women with GSM. In fact, less PM women use topical E than unregulated therapies with more uncertain claims of safety and efficacy. We earlier showed that compared to premenopausal women, vaginal epithelium from PM women has lower levels of desmoglein-1 (DSG1) and desmocollin-1 (DSC1), proteins contained in cell-cell adhesion molecules termed desmosomes. We also found similar loss of DSG1 and DSC1 in vaginal epithelium of ovariectomized (OVX) vs. ovary-intact mice, a change associated with loss of epithelial barrier function and greater susceptibility to genital infection. Conversely, treatment of OVX mice with topical E restored vaginal epithelial integrity and barrier protection. In follow-up studies, we showed that E increases vaginal expression of ephrin-A3 (EFNA3) and that EFNA3-mediated signaling promotes vaginal expression of DSG1 and DSC1. Together, these results indicated OVX mice precisely model vaginal epithelial barrier dysfunction seen in PM women and identified an exciting opportunity to use clinical and basic science investigation to define key regulators of vaginal epithelial health, including E-mediated regulation of ephrin-Eph signaling that promotes vaginal epithelial desmosome expression and vaginal epithelial barrier function. Aim 1 will use mice with keratin 5-driven tamoxifen-inducible Cre recombinase and floxed desmoplakin (a protein essential to desmosome structure) to define desmosome- mediated maintenance of vaginal epithelial integrity and vaginal epithelial barrier protection. Ensuring efficient completion of this aim, these mice are already generated in our lab. Aim 2 will also use mice to define ephrin- Eph signaling that regulates vaginal epithelial health, comparing vaginal moisture, epithelial barrier function, and pathogen susceptibility in wildtype OVX mice intravaginally treated with E or an EFNA3-mimetic agonist peptide (EFNA3-MAP) and the effects of EFNA3-MAP on vaginal epithelial barrier protection in OVX knockout mice lacking EphA2 receptors and OVX wildtype mice administered EphA2-blocking antibody or chemicals blocking EphA2-mediated signaling. Switching gears, Aim 3 will enroll 20 PM women with GSM to provide the first prospective evaluation of the effects of topical E on vaginal moisture, vaginal epithelial barrier function and other markers of vaginal epithelial health. Completing these studies will newly define E-mediated regulation of ephrin-Eph signaling that maintain vaginal epithelial barrier function and deliver scientifically sound rationale for greater uptake of topical E therapy by health care providers and PM women.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $393,750 )
2026	2026	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Aging Research	000	1	7/10/2026	NEW	$393,750
														Subtotal = $393,750

Grand Total All Awards = $393,750

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Using basic science and clinical research to define the molecular basis of vaginal epithelial dysfunction that negatively impacts reproductive health after menopause

Award Number: R56AG099541

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/15/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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