Project Details
Description
ABSTRACT
The genitourinary syndrome of menopause (GSM) affects most postmenopausal (PM) women. This syndrome,
caused by lower levels of circulating estrogen (E) in PM women, includes vaginal irritation, dyspareunia, and
recurrent urinary tract infection. While intravaginal administration of low-dose E alleviates signs and symptoms
of GSM, only about 10% of affected women receive this treatment. Contributing to limited acceptance of these
therapies by healthcare providers and women affected by the GSM are their black box warnings denoting an
increased risk of cardiovascular disease and endometrial cancer. Our research previously showed that genital
tissue from PM women and ovariectomized (OVX) mice display comparable loss of the desmosomal cadherins
desmoglein-1 (DSG1) and desmocollin-1 (DSC1), cell-cell adhesion molecules that promote epithelial integrity
and barrier function. More recently we created an EFNA3-mimetic agonist peptide (EFNA3-MAP) and saw its
intravaginal (ivag) administration to OVX mice restore genital epithelial barrier function and that its short-term
treatment in a strain of mouse commonly used to assess carcinogenicity does not induce tumor development.
The current proposal will explore three aims to define EFNA3-MAP mechanism of action, optimize its delivery
and ability to preserve genital epithelial barrier function, and establish the safety profile of long-term treatment.
The first aim will use OVX mice to demonstrate that ivag EFNA3-MAP treatment promotes genital epithelial
proliferation and differentiation and restores desmosomal cadherin expression and epithelial barrier function.
Other studies will use OVX mice and commercially available knockout mice to define EFNA-mediated signaling
pathways and capacity of ivag EFNA3-MAP treatment to reduce susceptibility to genital HSV-2 infection. The
second aim will define in vitro biocompatibility and in vivo efficacy of two separate ivag delivery systems with
the potential to enhance peptide persistence in genital mucosal tissue. These delivery systems are chitosan-
based gels that increase peptide mucoadhesion and bigels that allow aqueous hydrogel and oil-based delivery.
Other studies will use OVX mice to delineate EFNA3-MAP dosing schedules that optimize its ability to restore
genital epithelial barrier function. The third aim will use rasH2 mice to explore the carcinogenicity of long-term
ivag EFNA3-MAP treatment as this mouse strain effectively identifies agents that promote carcinogenesis and
provides carcinogenicity testing results accepted by key regulatory agencies. Together, these aims will provide
essential guidance for developing a novel nonsteroidal and nonhormonal compound that reverses the loss of
genital epithelial health associated with loss of circulating E, and we expect this proposal will define EFNA3-
MAP-mediated regulation of genital epithelial integrity and barrier function, identify specific delivery platforms
and dosing schedules that optimize genital epithelial health, and establish a favorable safety profile for long-
term ivag EFNA3-MAP administration.
Status | Active |
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Effective start/end date | 09/21/23 → 08/31/24 |
Funding
- National Institute on Aging: $391,101.00
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