Ovarian hormone-independent sex chromosome effects in menopause

说明（由申请人提供）：绝经后妇女代谢综合征、心血管和肾脏疾病的发病率高于绝经前妇女。为了开始发现导致绝经后妇女衰老不利影响的基因和途径，我们提出了两种不同的策略来发现可能导致绝经后妇女面临这些疾病风险增加的新基因和途径。我们将利用“四核心基因型”小鼠模型，在该模型中，性染色体效应可以从性腺性别中分离出来，从而使XX和XY动物之间的比较独立于它们是否具有卵巢（例如，XX-与XY-雌性）或睾丸（XX-与XY-雄性）。虽然最近对小鼠进行的微阵列研究表明，成千上万的基因受性腺激素的调节，但由性染色体补体独立于性腺激素调节的基因数量要有限得多。因此，我们期望在肾素血管紧张素系统（RAS）过度活跃的卵巢激素缺乏女性中发现少数基因（<10）受性染色体补体（SCC）的差异调节。Aim 1将使用一种紧密聚焦的微阵列方法，利用我们区分SCE和性腺性别的能力，识别在angii输注e2缺乏的女性中，肾脏中受SCC差异调节的基因。目的2将使用候选基因方法来验证卵巢切除术和高血压对肾脏组织特异性肾素血管紧张素系统（RAS）的调节是性染色体依赖的假设。我们推测，XX SCC与卵巢切除后e2缺乏状态之间的相互作用，通过增加血浆和肾脏中Ang II水平、Ang II合成酶、血管紧张素转换酶（ACE）与分解代谢酶的比例，使肾脏RAS的血管收缩/血管扩张平衡向血管收缩的程度大于xy女性。血管紧张素转换酶2 （ACE2）和1型血管紧张素受体（AT1R）与血管扩张剂2型血管紧张素受体（AT2R）的比值。

DESCRIPTION (provided by applicant): Postmenopausal women have a higher incidence of diseases such as metabolic syndrome, cardiovascular and renal disease than premenopausal women. To begin to uncover genes and pathways that contribute to these adverse effects of aging in the postmenopausal woman, we propose two distinct strategies for discovering novel genes and pathways that may contribute to the increased risk postmenopausal women face towards these diseases. We will take advantage of the "four core genotypes" mouse model in which sex chromosome effects can be separated from the gonadal sex thus enabling comparisons among XX and XY animals independently of whether they were born with ovaries (e.g., XX- vs. XY-females) or testes (XX- vs. XY-males). While recent microarray studies in mice have demonstrated that thousands of genes are regulated by gonadal hormones, the number of genes regulated by the sex chromosome complement independently of the gonadal hormones is far more limited. Thus, we expect to discover a handful of genes (<10) that are differentially regulated by the sex chromosome complement (SCC) in the ovarian hormone deficient female during over activity of the renin angiotensin system (RAS). Aim 1 will use a tightly focused microarray approach leveraging our ability to differentiate SCE from gonadal sex to identify genes in the kidney that are differentially regulated by the SCC in the Ang II infused E2-deficient female. Aim 2 will use a candidate gene approach to test the hypothesis that the regulation of the tissue-specific renin angiotensin system (RAS) in the kidney by ovariectomy and hypertension is sex chromosome dependent. We hypothesize that the interaction between the XX SCC with the E2-deficient state of ovariectomy tips the vasoconstrictor/vasodilator balance of the renal RAS towards vasoconstriction to a greater extent than in the XY-Female by increasing plasma and renal levels of Ang II, the ratio of the Ang II synthetic enzyme, angiotensin converting enzyme (ACE) to the catabolic enzyme, angiotensin converting enzyme 2 (ACE2) and the ratio of the type 1 angiotensin receptor (AT1R) to the vasodilator type 2 angiotensin receptor (AT2R). PUBLIC HEALTH RELEVANCE: This project is designed to make new discoveries into why postmenopausal women are at increased risk for diseases like metabolic syndrome, hypertension and cardiovascular disease compared to premenopausal women. We will make these new discoveries by studying sex chromosome effects independently of the ovarian hormones using a unique animal model in which we can separate, for the first time, sex chromosome differences between males (XY) and females (XX) from the sex hormone differences (e.g., differences in estrogen and testosterone levels). By discovering new genes and pathways responsible for the increased incidence of these diseases in ovarian deficient females, new therapeutic treatments are likely to ensue for post-menopausal women and women with ovarian hormone deficiency.