Ovary Intact Murine Model for Menopause

描述(申请人提供)：到2025年，19.5%的美国人口将是绝经后的老年妇女。许多健康风险都与更年期有关，因此，对女性更年期和衰老的研究是最有意义的。在相关的动物模型中研究与更年期相关的疾病将特别有用。职业化学物质4-乙烯基环己烯二环氧化物(VCD)已被很好地表征并发现通过加速闭锁(细胞凋亡)的自然过程而导致小鼠和大鼠的早熟卵巢衰竭。最近，初步数据表明，VCD诱导的小鼠卵泡丢失可以在每日服药后15天内导致原始卵泡枯竭。这会导致服药开始后46天内卵巢完全衰竭，动物保留剩余的卵巢组织。在VCD治疗的小鼠中观察到了与几种与更年期相关的疾病有关的生理终点，包括骨质疏松症、心血管疾病和卵巢癌。大多数女性进入更年期是因为卵巢功能逐渐衰竭，她们保留了剩余的卵巢组织。因此，一个卵泡耗尽、卵巢完整的动物将最接近地模拟从围绝经期到绝经后生命阶段的自然过程。这里建议进行研究，以更全面地描述已经看到的生理终点。需要检验的假设是，VCD治疗的小鼠将作为一个高度相关的动物模型，用于旨在了解更年期许多方面的研究。已经提出了四个特定目标：特定目标1：确定即将发生的卵巢衰竭时期周围的事件(围绝经期模型)；特定目标2：研究骨钙素水平升高的机制(骨质疏松模型)；特定目标3：描述主动脉病变的发展特征(心血管疾病模型)；特定目标4：评估卵巢表面上皮细胞增殖引起的变化(卵巢癌模型)。这里提出的研究将在卵泡耗尽、卵巢完整的小鼠身上提供证据，说明更年期生理和病理的哪些方面与设计针对机制或治疗问题的未来研究特别相关。因此，VCD治疗的小鼠的特征将对更年期相关病理学的研究做出深刻贡献，从而对妇女的健康也有重大贡献。

DESCRIPTION (provided by applicant): By the year 2025, 19.5% of the population of the U.S. will be post-menopausal aged women. Many health risks are associated with menopause, thus, research into menopause and aging in women is of prime interest. Investigations of menopause-associated disorders in a relevant animal model would be particularly useful. The occupational chemical 4-vinylcyclohexene diepoxide (VCD) has been well characterized and found to induce pre-mature ovarian failure in mice and rats by accelerating the natural process of atresia (apoptosis). More recently, preliminary data have demonstrated that VCD-induced follicle loss in mice can cause depletion of primordial follicles within 15 days of daily dosing. This results in complete ovarian failure within 46 days of the onset of dosing, and the animals retain residual ovarian tissue. Physiological end points related to several menopause-associated disorders, including osteoporosis, cardiovascular disease, and ovarian cancer have been observed in VCD-treated mice. The majority of women enter menopause by a gradual depletion of ovarian function and they retain residual ovarian tissue. Thus, a follicle-deplete, ovary-intact animal would most closely mimic the natural progression through peri-menopause and into the post-menopausal stage of life. It is proposed here to conduct studies to more completely characterize the physiological end points that have already been seen. The hypothesis to be tested is that the VCD-treated mouse will serve as a highly relevant animal model for studies aimed at understanding many of the facets of menopause. Four Specific Aims have been proposed: Specific Aim 1: To determine events surrounding the period of impending ovarian failure (model for peri-menopause) Specific Aim 2: To investigate mechanisms by which osteocalcin levels are elevated (model for osteoporosis) Specific Aim 3: To characterize the development of aortic lesions (model for cardiovascular disease) Specific Aim 4: To evaluate changes resulting from proliferation of the ovarian surface epithelium (model for ovarian cancer). The studies proposed here will provide evidence in the follicle-deplete, ovary-intact mouse as to what aspects of menopausal physiology and pathology are particularly relevant for designing future studies aimed at mechanistic or therapeutic issues. Characterization of the VCD-treated mouse will, therefore, make a profound contribution to the study of menopause-related pathologies and, therefore, to women's health.