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: 7278154
• 负责人: Jay Ross Kaplan
• 金额: $ 53.73万
• 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/7278154
• 关键词: 4-vinyl-1-cyclohexene dioxide; Affect; American; Androgens; Animal Model; Animals; Atherosclerosis; Breast; Cardiovascular Diseases; Cause of Death; Cell Proliferation; Characteristics; Chronic Disease; Classification; Complex; Condition; Data; Development; Disease; Early Intervention; Estradiol; Estrogens; Exposure to; Failure; Follicle Stimulating Hormone; Fracture; Hormonal; Hormonal Change; Hormones; Human; Individual; Individual Differences; Intervention; Investigation; Life; Lipids; Lipoproteins; Macaca fascicularis; Menopause; Modeling; Monkeys; Mus; Numbers; Osteoporosis; Ovarian; Ovarian Follicle; Ovarian hormone; Ovariectomy; Ovary; Pathogenesis; Pattern; Perimenopause; Physiological; Pituitary Gland; Plasma; Population; Postmenopause; Primordial Follicle; Procedures; Process; Production; Progesterone; Quality of life; Relative (related person); Research; Research Personnel; Residual state; Role; Staging; Study models; Techniques; Testing; Testosterone; Thinking; Tissues; Woman; bone loss; cardiovascular risk factor; design; improved; indexing; inhibin; inhibin B; malignant breast neoplasm; nonhuman primate; programs; reproductive

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，每七个美国人中就有一个是绝经后妇女。心血管疾病将是这一群体中最大的单一死亡原因，多达一半的人将遭受与糖尿病有关的骨折，十分之一的人将发展为乳腺癌。生殖生命阶段和这些更年期相关疾病的发病之间的关系尚未得到充分探讨，在很大程度上，因为缺乏一个合适的动物模型的自然绝经的妇女。我们建议将在小鼠中开发的一种技术扩展到食蟹猴（Macaca fascicularis），该技术使用暴露于4-乙烯基环己烯二环氧化物（VCD）来选择性地靶向原始卵泡和初级卵泡，从而诱导卵巢衰竭并模拟女性发生的更年期。我们假设，具有产生卵泡的卵泡耗竭卵巢（我们称之为“残余卵巢绝经”[ROM]）的猴子将模仿自然绝经后妇女的疾病脆弱性。总体目标是使用ROM和卵巢切除（OVX）猴，以确定慢性疾病的发展过程中的绝经期过渡期相比，绝经后时期。其目标是： 具体目标1。比较和对比卵巢卵泡缺失的猴子与卵巢切除的猴子的激素特征。 具体目标2。确定在围绝经期过渡期间动脉粥样硬化易感性增加的程度，以及在ROM和OVX处理条件下观察到的心血管风险因素或卵巢激素变化与易感性增加的关系。 具体目标3。确定围绝经期过渡期间骨丢失的脆弱性增加的程度，以及任何此类增加如何与ROM和OVX动物中观察到的垂体和卵巢激素变化相关。 具体目标4。为了确定是否以及在何种程度上，血浆雄激素浓度调节雌二醇刺激的乳腺细胞增殖的ROM猴相比，其OVX同行。相关性：据推测，绝经期妇女易患主要影响绝经后妇女的疾病，特别是心血管疾病和骨质疏松症的风险增加;这种增加（拟议的研究旨在检测）意味着需要积极的早期干预。此外，据推测，自然绝经妇女的卵巢基质产生大量的睾酮，这反过来可能会减缓骨丢失、动脉粥样硬化的进展，可能还会减缓乳腺癌的发生。通过确定绝经前和绝经后妇女的残留激素对这些疾病过程的影响程度，拟议的研究将有助于开发有针对性的个性化治疗方法，以改善绝经后的生活质量。