Ovarian hormone-independent sex chromosome effects in menopause

描述(申请人提供)：绝经后女性的代谢综合征、心血管和肾脏疾病等疾病的发病率高于绝经前女性。为了开始揭示导致绝经后妇女衰老的这些不利影响的基因和途径，我们提出了两种不同的策略，以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“四种核心基因类型”的小鼠模型，在该模型中，性染色体效应可以从性腺性别中分离出来，从而能够在XX和XY动物之间进行比较，而无论它们出生时是卵巢(例如，XX-雌性与XY-雌性)还是睾丸(XX-XY-雄性)。虽然最近对小鼠的微阵列研究表明，数千个基因受性腺激素调控，但受性染色体互补调控的基因数量远远有限，而不受性腺激素的影响。因此，我们希望在卵巢激素缺乏的女性中发现一些在肾素血管紧张素系统(RAS)过度活动期间受性染色体互补(SCC)差异调节的基因(&lt；10)。目标1将使用一种紧密聚焦的微阵列方法，利用我们区分姐妹染色单体交换和性腺性别的能力，在注射了血管紧张素II的E2缺陷女性中，识别肾脏中受干细胞差异调控的基因。目的2将使用候选基因方法来验证这样的假设，即卵巢切除和高血压对肾脏组织特异性肾素血管紧张素系统(RAS)的调节是性别染色体依赖性的。我们假设XX SCC与卵巢切除的E2缺乏状态之间的相互作用，通过增加血浆和肾脏Ang II水平、Ang II合成酶、血管紧张素转换酶(ACE)与分解代谢酶、血管紧张素转换酶2(ACE2)的比率以及1型血管紧张素受体(AT1R)与血管扩张因子2型受体(AT2R)的比率，使肾RAS的血管收缩/血管扩张平衡向血管收缩的方向倾斜。 与公共健康相关：该项目旨在对为什么绝经后女性比绝经前女性患代谢综合征、高血压和心血管疾病等疾病的风险更高做出新的发现。我们将通过使用一种独特的动物模型来研究性染色体对卵巢激素的影响，从而做出这些新的发现。在这种动物模型中，我们可以首次将男性(XY)和女性(XX)之间的性染色体差异与性激素差异(例如，雌激素和睾酮水平的差异)分开。通过发现导致卵巢缺陷女性这些疾病发病率增加的新基因和途径，新的治疗方法可能会接踵而至，用于绝经后妇女和卵巢激素缺乏的妇女。

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.