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.

抽象的 更年期泌尿生殖综合征 (GSM) 影响大多数绝经后 (PM) 女性。这种综合症， 由 PM 女性循环雌激素 (E) 水平较低引起，包括阴道刺激、性交困难和 反复尿路感染。阴道内给予低剂量 E 可缓解体征和症状 在 GSM 中，只有约 10% 的受影响女性接受这种治疗。有助于有限地接受这些 医疗保健提供者和受 GSM 影响的妇女的治疗是他们的黑匣子警告，表明 心血管疾病和子宫内膜癌的风险增加。我们之前的研究表明，生殖器 PM 女性和卵巢切除 (OVX) 小鼠的组织显示桥粒钙粘蛋白的类似损失 desmoglein-1 (DSG1) 和 desmocollin-1 (DSC1)，促进上皮完整性的细胞间粘附分子 和屏障功能。最近，我们创建了一种 EFNA3 模拟激动剂肽 (EFNA3-MAP)，并看到了其 对 OVX 小鼠进行阴道内 (ivag) 给药可恢复生殖器上皮屏障功能，并且其短期效果 对通常用于评估致癌性的小鼠品系进行治疗不会诱导肿瘤发展。 当前提案将探讨三个目标，以定义 EFNA3-MAP 的作用机制、优化其交付 和保护生殖器上皮屏障功能的能力，并建立长期治疗的安全性。 第一个目标将使用 OVX 小鼠证明 ivag EFNA3-MAP 治疗可促进生殖器上皮细胞 增殖和分化并恢复桥粒钙粘蛋白表达和上皮屏障功能。 其他研究将使用 OVX 小鼠和市售的基因敲除小鼠来定义 EFNA 介导的信号传导 ivag EFNA3-MAP 治疗降低生殖器 HSV-2 感染易感性的途径和能力。这 第二个目标将定义两个独立的 ivag 递送系统的体外生物相容性和体内功效 增强肽在生殖器粘膜组织中持久性的潜力。这些递送系统是壳聚糖- 基于凝胶可增加肽粘膜粘附力，而大凝胶可允许水性水凝胶和油基递送。 其他研究将使用 OVX 小鼠来制定 EFNA3-MAP 给药方案，以优化其恢复能力 生殖器上皮屏障功能。第三个目标是利用rasH2小鼠来探索长期使用的致癌性。 ivag EFNA3-MAP 治疗，因为该小鼠品系可有效识别促进癌变和 提供主要监管机构认可的致癌性测试结果。这些目标共同将提供 开发一种新型非甾体和非激素化合物以逆转失去的重要指导 生殖器上皮健康与循环 E 损失相关，我们预计该提案将定义 EFNA3- MAP 介导的生殖器上皮完整性和屏障功能的调节，确定特定的递送平台 优化生殖器上皮健康的给药方案，并为长期治疗建立良好的安全性。 术语 ivag EFNA3-MAP 给药。