Role of the Follicle-Depleted Ovary in the Pathogenesis of Chronic Diseases

卵泡耗尽的卵巢在慢性疾病发病机制中的作用

• 批准号: 7075609
• 负责人: Jay Ross Kaplan
• 金额: $ 54.6万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7075609
• 关键词: Macaca fascicularis; atherosclerosis; biological models; blood lipid; breast neoplasms; cancer risk; carcinogens; cardiovascular disorder risk; cell proliferation; cyclohexanes; estradiol; follicle stimulating hormone; graafian follicles; hormone regulation /control mechanism; luteinizing hormone; mammary gland; menopause; osteoporosis; ovariectomy; pathologic process; postmenopause; testosterone

DESCRIPTION (provided by applicant): Within a decade one of every seven Americans will be a postmenopausal woman. Cardiovascular disease will be the largest single cause of death within this group, up to half will suffer an osteoporosis-related fracture, and one in ten will develop breast cancer. The relationship between stage of reproductive life and the onset of these menopause-associated diseases has not been explored adequately, in large part, because of the lack of a suitable animal model of natural menopause in women. We propose to extend to cynomolgus monkeys (Macaca fascicularis) a technique developed in mice that uses exposure to 4-vinylcyclohexene diepoxide (VCD) to selectively target primordial and primary follicles, thereby inducing ovarian failure and modeling the menopause as it occurs in women. We hypothesize that monkeys with a hormone-producing, follicle-depleted ovary (a condition that we refer to as "residual ovary menopause" [ROM]) will mimic the disease vulnerability of naturally postmenopausal women. The overall objective is to use ROM and ovariectomized (OVX) monkeys to determine the development of chronic disease processes during the perimenopausal transition compared to the postmenopausal period. The aims are: Specific Aim 1. To compare and contrast the hormonal characteristics of monkeys with follicle-depleted ovaries with those observed in their ovariectomized counterparts. Specific Aim 2. To determine the extent to which vulnerability to atherosclerosis is increased during the perimenopausal transition and how any such increase in vulnerability is related to changes in cardiovascular risk factors or ovarian hormones observed among animals in the ROM and OVX treatment conditions. Specific Aim 3. To determine the extent to which vulnerability to bone loss is increased during the perimenopausal transition and how any such increase is related to the pituitary and ovarian hormonal changes observed among ROM and OVX animals. Specific Aim 4. To determine if and to what extent plasma androgen concentrations modulate estradiol-stimulated breast cell proliferation in ROM monkeys in comparison to their OVX counterparts. Relevance: It has been speculated that there is a perimenopausal increase in vulnerability to the diseases that prominently affect postmenopausal women, especially cardiovascular disease and osteoporosis; such an increase (which the proposed research is designed to detect) implies the need for vigorous early intervention. Further, it has been speculated that the ovarian stroma of naturally menopausal women produces a significant -though variable- amount of testosterone, which in turn may moderate the progression of bone loss, atherosclerosis, and perhaps the occurrence of breast cancer. By determining the extent to which the residual hormones of peri- and postmenopausal women influence these disease processes, the proposed research will facilitate the development of targeted, individualized therapies for improving the postmenopausal quality of life.

描述（由申请人提供）：在十年内，每七个美国人中的一个将是绝经后的妇女。心血管疾病将是这一组中最大的单一死亡原因，多达一半的骨质疏松症将遭受与骨质疏松相关的骨折，十分之一的人会患上乳腺癌。在很大程度上，由于缺乏合适的女性自然更年期动物模型，生殖生活阶段与这些更年期相关疾病的发作之间的关系尚未得到充分探索。我们建议将一种在小鼠中开发的技术延伸到cynomolgus猴子（Macaca fascicularis），该技术使用暴露于4-乙烯基环己烯二氧化碳（VCD），以选择性地靶向原始卵泡和原代卵泡，从而诱导卵巢衰竭，并在女性中造成卵巢衰竭，并在女性中造成更新。我们假设具有产生激素的卵泡卵巢的猴子（我们称之为“残留的卵巢更年期” [ROM]的疾病将模仿天然绝经后妇女的疾病脆弱性。总体目的是使用ROM和卵巢切除术（OVX）猴子来确定与绝经后时期的围绝经期临床过渡期间慢性疾病过程的发展。目的是： 特定的目的1。要比较和对比猴子的荷尔蒙特征与卵泡耗血的卵巢与在卵巢切除术中观察到的卵巢。 具体目的2。确定围绝经内部过渡期间对动脉粥样硬化的脆弱性的程度，以及脆弱性的任何这种增加与在ROM和OVX治疗条件下观察到的动物中的心血管危险因素或卵巢激素的变化有关。 特定目的3。确定围绝经期转变期间增加骨质流失的脆弱性，以及任何这种增加与垂体和卵巢激素变化如何相关的ROM和OVX动物之间的变化。 具体目的4。确定与OVX对应物相比，ROM猴子中的雌二醇雄激素浓度是否以及在多大程度上调节雌二醇刺激的乳腺细胞增殖。相关性：据推测，对疾病的脆弱性会增加，这些疾病显着影响绝经后妇女，尤其是心血管疾病和骨质疏松症。这样的增加（拟议的研究旨在检测到这一点）意味着需要进行剧烈的早期干预。此外，据推测，自然绝经妇女的卵巢基质产生了显着的 - 尽管睾丸激素量可变，而睾丸激素可能会导致骨骼损失，动脉粥样硬化以及乳腺癌的发生。通过确定绝经后妇女的残留激素影响这些疾病过程的程度，拟议的研究将促进有针对性的个性化疗法的发展，以改善绝经后的生活质量。