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.

我们最近报道说，卵巢类固醇雌二醇（E2）降低了垂体和肾上腺中的血管紧张素1型受体（AT1R）结合，并减少血管紧张素II（ANG IL）诱导 NACI剥夺，卵巢切除（OVX）大鼠的肾上腺皮质激素（ACTH）和醛固酮分泌。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体，而这些疾病在女性中的进展速度要比男性迅速。因此，醛固酮分泌的卵巢类固醇衰减可能是保护女性免受心血管和肾脏疾病的一种机制。尽管我们的发现清楚地表明E2对ANG II的肾上腺反应性调节，但尚不清楚卵巢衰老本身对ANG II的肾上腺反应性的影响。在该提案中要检验的中心假设是，随着卵巢衰老而发生的循环类固醇的降低会导致对ANG II的肾上腺反应性提高，并且可以通过适当的激素替代治疗（HRT）进行标准化。我们假设，随着卵巢衰老而发生的卵巢类固醇水平的下降导致通过增加对ANG II的肾上腺醛固酮反应来增加患心血管和肾脏疾病的风险，我们假设适当的HRT可以扭转这种风险。在拟议的研究的目标1中，我们将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，通过检查年轻（6个月），循环和旧（24个月），非自由的Fischer Fischer 3444亿鼠大鼠。 Fischer 344亿只大鼠是美国国家衰老研究所推荐的啮齿动物衰老模型。在AIM 2中，我们将确定垂直于垂体和肾上腺AT1R结合以及ACTH和ACTH和醛固酮对ANG II的HRT方案老年大鼠在年轻的骑自行车大鼠中观察到的水平。我们将研究垂体和肾上腺AT1R结合，ACTH以及ACTH和醛固酮对ANG II的反应，在旧的未经处理的大鼠中以及用E2，孕酮（P4），E2和P4合并的旧大鼠中，或与雌激素受体Alpha或Beta选择性调制器中的一种。这些研究将确定卵巢衰老是否导致对ANG II的肾上腺反应性缺陷，并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提供初步数据，以提交有关此主题的未来个人研究项目赠款（R01）申请。