Developing a nonsteroidal and nonhormonal agent that reverses menopause-related loss of genital epithelial integrity and function

开发一种非类固醇和非激素药物，可逆转更年期相关的生殖器上皮完整性和功能丧失

• 批准号: 10901049
• 负责人: Thomas L. Cherpes
• 金额: $ 39.11万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-21 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10901049
• 关键词: Affect; Agonist; Biology; Blocking Antibodies; Cadherins; Carcinogenicity Tests; Cardiovascular Diseases; Cell Adhesion Molecules; Cell Differentiation process; Cell-Cell Adhesion; Chemicals; Chitosan; Chronic; Cream; Data; Dementia; Desmosomes; Development; Dose; Dyspareunia; Dysuria; Effectiveness; Endometrial Carcinoma; Eph Family Receptors; EphA2 Receptor; EphA4 Receptor; Ephrin-A3; Epithelium; Estrogens; Gel; Genital; Genitalia; Genitourinary system; Goals; Health; Health Personnel; Human; Human Herpesvirus 2; Hydrogels; Impairment; In Vitro; Infection; Inflammation; Intravaginal Administration; Invaded; Knockout Mice; Learning; Long-Term Effects; Mediating; Menopausal Syndrome; Menopause; Modeling; Mouse Strains; Mucous Membrane; Mus; Neoplasms; Oils; Ovary; Pathogenesis; Peptides; Postmenopause; Predisposition; Premenopause; Production; Progestins; Proliferating; RAS genes; Recurrence; Regulation; Reporting; Research; Risk Assessment; Role; Safety; Saline; Schedule; Signal Pathway; Signal Transduction; Signs and Symptoms; Syndrome; System; Test Result; Testing; Therapeutic; Tissues; Transgenic Organisms; Tumor Promotion; Tumor Suppression; Urinary tract infection; Vagina; Weight; Woman; Work; aqueous; base; biomaterial compatibility; carcinogenesis; carcinogenicity; cardiovascular disorder risk; desmocollin; desmoglein 1; experimental study; hypothalamic pituitary ovarian axis; in vivo; inhibitor; insight; irritation; mimetics; mouse model; novel; pathogenic microbe; polypeptide; preservation; tumor

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.

摘要