Ovarian hormone-independent sex chromosome effects in menopause

描述（由申请人提供）：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良影响的基因和途径，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的风险增加的新基因和途径。我们将利用“四个核心基因型”小鼠模型，其中性染色体效应可以与性腺性别分离，从而能够在XX和XY动物之间进行比较，而不依赖于它们是否出生时具有卵巢（例如，XX- vs. XY-雌性）或睾丸（XX- vs. XY-雄性）。虽然最近对小鼠的微阵列研究表明，数千个基因受到性腺激素的调节，但独立于性腺激素的性染色体互补调节的基因数量要有限得多。因此，我们期望发现少数基因（<10个）在卵巢激素缺乏的女性中，在肾素血管紧张素系统（RAS）过度活性期间，受到性染色体补体（SCC）的差异调节。目的1将使用一种紧密聚焦的微阵列方法，利用我们区分SCE与性腺性别的能力，以鉴定在血管紧张素II输注的E2缺陷女性中由SCC差异调节的肾脏基因。目的2：利用候选基因的方法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性的假说。我们假设XX SCC与卵巢切除术的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）与分解代谢酶的比率、血管紧张素转化酶2（ACE 2）和1型血管紧张素受体（AT 1 R）与血管扩张剂2型血管紧张素受体（AT 2 R）的比率。 公共卫生相关性：该项目旨在对为什么绝经后妇女与绝经前妇女相比患代谢综合征，高血压和心血管疾病的风险增加进行新的发现。我们将通过使用独特的动物模型独立于卵巢激素研究性染色体效应来做出这些新发现，在该动物模型中，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）。通过发现新的基因和途径，这些疾病的发病率增加卵巢缺陷的女性，新的治疗方法可能会随之而来的绝经后妇女和卵巢激素缺乏症的妇女。

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.