Ovary Intact Murine Model for Menopause

描述（由申请人提供）：到2025年，19.5%的美国人口将是绝经后的老年妇女。许多健康风险与更年期有关，因此，对女性更年期和衰老的研究是最感兴趣的。在相关的动物模型中调查绝经相关疾病将特别有用。职业化学物质4-乙烯基环己烯二氧化物（VCD）已经被很好地表征并发现通过加速自然闭锁（细胞凋亡）过程诱导小鼠和大鼠卵巢早衰。最近，初步数据表明，vcd诱导的小鼠卵泡丢失可在每天给药15天内导致原始卵泡衰竭。这导致在给药后46天内卵巢完全衰竭，动物保留残留的卵巢组织。在vcd治疗的小鼠中观察到与几种绝经相关疾病相关的生理终点，包括骨质疏松症、心血管疾病和卵巢癌。大多数妇女进入更年期卵巢功能的逐渐枯竭，他们保留残余的卵巢组织。因此，卵泡减少，卵巢完整的动物将最接近地模拟自然进程，从围绝经期到绝经后的生活阶段。这里建议进行研究，以更完整地表征已经看到的生理终点。需要验证的假设是，vcd治疗的小鼠将作为一种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：确定围绕即将发生的卵巢衰竭时期的事件（围绝经期模型）特定目标2：研究骨钙素水平升高的机制（骨质疏松症模型）特定目标3：表征主动脉病变的发展（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、卵巢完整的小鼠中提供证据，说明更年期生理和病理的哪些方面与设计未来的机制或治疗问题的研究特别相关。因此，对vcd处理小鼠的特征描述将对绝经相关病理的研究做出深远的贡献，从而对妇女的健康做出贡献。

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.