Ovarian Senescence and Adrenal Hormone Responses

卵巢衰老和肾上腺激素反应

基本信息

批准号：
6895538
负责人：
DARREN M ROESCH
金额：
$ 7.76万
依托单位：
GEORGETOWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-06-01 至 2007-04-30
项目状态：
已结题

项目摘要

We have recently reported that the ovarian steroid estradiol (E2) reduces angiotensin type 1 receptor (AT1R) binding in the pituitary and adrenal and attenuates angiotensin II (Ang il)-induced adrenocorticotropic hormone (ACTH) and aldosterone secretion in NaCI-deprived, ovariectomized (OVX) rats. Clinical and experimental data suggest aldosterone is mediator of the progression of cardiovascular and renal disease, and these diseases are known to progress less rapidly in women than in men. Therefore, ovarian steroid attenuation of aldosterone secretion may be one mechanism by which females are protected from cardiovascular and renal disease. Although our findings clearly indicate that E2 regulates adrenal responsiveness to Ang II, the effect of ovarian senescence per se on adrenal responsiveness to Ang II is not known. The central hypothesis to be tested in this proposal is that the decrease in circulating steroids that occurs with ovarian senescence leads to an increase in adrenal responsiveness to Ang II that can be normalized with appropriate hormone replacement therapy (HRT). We hypothesize that the decline in circulating ovarian steroid levels that occurs with ovarian senescence leads to an increased risk of developing cardiovascular and renal disease by increasing adrenal aldosterone responses to Ang II, and we hypothesize appropriate HRT can reverse this risk. In Aim 1 of the proposed research, we will characterize the effect of ovarian senescence on pituitary and adrenal AT1R binding and Ang II-induced ACTH and aldosterone responses by examining these variable in young (6 month), cycling and old (24 month), noncycling Fischer 344BN rats. The Fischer 344BN rat is a rodent model of aging that has been recommended by the National Institute on Aging. In Aim 2, we will determine the HRT regimen required to normalize pituitary and adrenal AT1R binding and ACTH and aldosterone responses to Ang II in old, noncycling rats to the levels observed in young, cycling rats. We will study pituitary and adrenal AT1R binding and ACTH and aldosterone responses to Ang II in young rats, in old untreated rats, and in old rats treated with E2, progesterone (P4), E2 and P4 combined, or with one of the estrogen receptor alpha or beta selective modulators. These studies will determine whether ovarian senescence leads to a defect in adrenal responsiveness to Ang II and will help determine which type of HRT is a viable option for normalizing adrenal function. It is anticipated that the results of these studies will provide preliminary data for submission of a future individual research project grant (R01) application on this topic.

我们最近报道，卵巢类固醇雌二醇 (E2) 可减少垂体和肾上腺中血管紧张素 1 型受体 (AT1R) 的结合，并减弱血管紧张素 II (Ang il) 诱导的剥夺 NaCl 的卵巢切除 (OVX) 大鼠中促肾上腺皮质激素 (ACTH) 和醛固酮的分泌。临床和实验数据表明醛固酮是心血管和肾脏疾病进展的介质，并且已知这些疾病在女性中的进展速度慢于男性。因此，卵巢类固醇减弱醛固酮分泌可能是保护女性免受心血管和肾脏疾病的一种机制。尽管我们的研究结果清楚地表明E2调节肾上腺对Ang II的反应性，但卵巢衰老本身对肾上腺对Ang II的反应性的影响尚不清楚。该提案要测试的中心假设是，随着卵巢衰老而发生的循环类固醇减少会导致肾上腺对 Ang II 的反应性增加，而这种反应性可以通过适当的激素替代疗法 (HRT) 恢复正常。我们假设随着卵巢衰老而发生的循环卵巢类固醇水平下降导致通过增加肾上腺醛固酮对 Ang II 的反应，增加患心血管和肾脏疾病的风险，我们假设适当的 HRT 可以逆转这种风险。在拟议研究的目标 1 中，我们将通过检查年轻（6 个月）、循环和老年（24 个月）的这些变量来表征卵巢衰老对垂体和肾上腺 AT1R 结合以及 Ang II 诱导的 ACTH 和醛固酮反应的影响。非循环 Fischer 344BN 大鼠。 Fischer 344BN 大鼠是美国国家衰老研究所推荐的衰老啮齿动物模型。在目标 2 中，我们将确定使垂体和肾上腺 AT1R 结合以及 ACTH 和醛固酮对 Ang II 的反应正常化所需的 HRT 方案。年老的、不骑自行车的老鼠的水平达到了年轻的、骑自行车的老鼠中观察到的水平。我们将研究年轻大鼠、未治疗的老年大鼠以及用 E2、孕酮 (P4)、E2 和 P4 组合或与其中一种雌激素受体治疗的老年大鼠的垂体和肾上腺 AT1R 结合以及 ACTH 和醛固酮对 Ang II 的反应α或β选择性调节剂。这些研究将确定卵巢衰老是否会导致肾上腺对 Ang II 的反应性缺陷，并将有助于确定哪种类型的 HRT 是使肾上腺功能正常化的可行选择。预计这些研究的结果将为提交有关该主题的未来个人研究项目拨款（R01）申请提供初步数据。