Ovarian hormone-independent sex chromosome effects in menopause

绝经期卵巢激素独立性染色体效应

• 批准号: 7979995
• 负责人: HONG JI
• 金额: $ 15.35万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7979995
• 关键词: Abbreviations; Adult; Adverse effects; Age; Aging; Angiotensin II; Animal Model; Animals; Blood Pressure; Breeding; Candidate Disease Gene; Cardiovascular Diseases; Cardiovascular system; Disease; Enzymes; Equilibrium; Estradiol; Estrogens; Exhibits; Experimental Models; Face; Female; Functional disorder; Genes; Genotype; Goals; Gonadal Hormones; Gonadal Steroid Hormones; Gonadal structure; Hypertension; Hypotension; Incidence; Infusion procedures; Kidney; Kidney Diseases; Menopause; Metabolic Syndrome X; Metabolic syndrome; Modeling; Mus; Ovarian; Ovarian hormone; Ovariectomy; Ovary; Pathway interactions; Peptidyl-Dipeptidase A; Plasma; Ploidies; Postmenopause; Premenopause; Receptor, Angiotensin, Type 1; Regulation; Renin-Angiotensin System; Reporting; Research; Risk; Role; Science; Sex Chromosomes; Testing; Testis; Testosterone; Time; Tissues; Type 2 Angiotensin II Receptor; Vasoconstrictor Agents; Vasodilator Agents; Woman; Women' s Health; combat; design; disorder risk; dosage; hormone deficiency; male; mouse model; novel; novel therapeutics; pressure; public health relevance; response; sex; sodium-chloride cotransporter; synthetic enzyme; vasoconstriction

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.

描述（申请人提供）：绝经后女性比绝经前女性有更高的代谢综合征、心血管和肾脏疾病等疾病的发病率。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开，从而能够在 XX 和 XY 动物之间进行比较，而不管它们是否出生时有卵巢（例如，XX- 与 XY-女性）或睾丸（XX- 与 XY-男性）。虽然最近对小鼠进行的微阵列研究表明，数千个基因受性腺激素调节，但独立于性腺激素的性染色体补体调节的基因数量要有限得多。因此，我们期望在卵巢激素缺乏的女性肾素血管紧张素系统（RAS）过度活动期间发现少数基因（<10）受到性染色体补体（SCC）的差异调节。目标 1 将使用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，来识别肾脏中受 Ang II 输注的 E2 缺陷女性中的 SCC 差异调节的基因。目标 2 将使用候选基因方法来检验以下假设：卵巢切除和高血压对肾脏中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。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的 Ang II 水平，使肾脏 RAS 的血管收缩/血管舒张平衡比 XY 女性更大程度地倾向于血管收缩。 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) 与血管舒张剂 2 型血管紧张素受体 (AT2R) 的关系。 公共健康相关性：该项目旨在发现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。我们将通过使用独特的动物模型研究独立于卵巢激素的性染色体效应，从而获得这些新发现，在该模型中，我们首次将男性（XY）和女性（XX）之间的性染色体差异与性激素差异分开（例如，雌激素和睾酮水平的差异）。通过发现卵巢缺陷女性中这些疾病发病率增加的新基因和途径，可能会为绝经后女性和卵巢激素缺乏的女性带来新的治疗方法。