HORMONE RECEPTORS AND MECHANISMS OF HORMONE ACTION

激素受体和激素作用机制

基本信息

批准号：
5225717
负责人：
THOMAS COSTIN REGISTER
金额：
--
依托单位：
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

项目摘要

Coronary heart, osteoporosis, and breast and uterine cancers have a significant impact on the health of women in their peri- and postmenopausal years. Heart disease is the leading cause of death among women, while osteoporosis is a debilitating disease affecting 30% to 50% of all postmenopausal women. Estrogen replacement in peri- and post- menopausal women reduces the risk of heart disease and osteoporosis by 50% or more. Unfortunately, estrogen replacement alone may increase the risk of endometrial and breast cancers. The addition of an opposing progestin reduces the risk of endometrial cancer without appearing to reduce the beneficial effects of estrogen on bone. However, the addition of a progestin may negate the heart-protective effect of estrogen and may have harmful effects on breast as well. The mechanism(s) behind these tissue- specific effects are not known. Estrogen, progesterone, and androgens modulate gene transcription through interaction with specific hormone receptors. Some of these hormone receptors have been identified in breast, uterus, artery and bone (as well as other tissues). We hypothesize that the tissue-specific effects of different hormone therapies are mediated primarily through differential modulation of the expression of the receptors for estrogen, progesterone, and androgens. Unfortunately, regulation of the expression of these hormone receptors is poorly understood in reproductive tissues and virtually unknown in arterial and skeletal tissues. We propose to determine steroid hormone receptor expression in breast, uterus, artery, and bone using a unique set of tissues available in our tissue bank. These tissues were derived from a set of ovariectomized female cynomolgus macaques that had been treated with 1) conjugated equine estrogens alone (CEE), 2) a progestin alone (medroxyprogesterone acetate, MPA), 3) the combination therapy (CEE + MPA), or 4) the anti-estrogen tamoxifen. The objectives are to determine hormone receptor expression, the location and types of receptor-positive cells, and the influences of individual hormone therapies on receptor expression in these tissues. Immunohistochemical analysis will be utilized to localize estrogen receptor, progesterone receptor, and androgen receptor positive cells in bone and artery sections, and to examine androgen receptor expression in mammary and uterine tissues. Hormone receptor mRNA expression will also be determined in each of these tissues. The results will provide valuable new information regarding the expression of individual receptors in these target tissues and the mechanisms of tissue-specific effects of different hormone regimens. These studies will have important implications for the health of postmenopausal women, and will further define the cynomolgus macaque as a model of women's health.

冠心病、骨质疏松症、乳腺癌和子宫癌对妇女围产期和围产期健康影响重大绝经后几年。心脏病是导致人群死亡的主要原因女性，而骨质疏松症是一种使人衰弱的疾病，影响 30% 至 50% 的女性所有绝经后妇女。围产期和产后雌激素替代更年期女性患心脏病和骨质疏松症的风险降低 50% 或更多。不幸的是，单独补充雌激素可能会增加风险子宫内膜癌和乳腺癌。添加相反的孕激素降低子宫内膜癌的风险，但似乎不会降低雌激素对骨骼的有益作用。然而，添加一个孕激素可能会抵消雌激素的心脏保护作用，并可能对乳房也有不良影响。这些组织背后的机制- 具体效果尚不清楚。雌激素、孕激素和雄激素通过以下方式调节基因转录：与特定激素受体的相互作用。其中一些激素受体已在乳房、子宫、动脉和骨骼（以及和其他组织一样）。我们假设组织特异性效应不同的激素疗法主要通过差异介导调节雌激素、孕激素受体的表达，和雄激素。不幸的是，这些表达的调节对生殖组织中的激素受体知之甚少，在动脉和骨骼组织中几乎未知。我们建议确定乳房中类固醇激素受体的表达，使用我们提供的一套独特的组织来切割子宫、动脉和骨骼组织库。这些组织来自一组切除卵巢的已用 1) 结合马治疗的雌性食蟹猴单独的雌激素（CEE），2）单独的孕激素（醋酸甲羟孕酮， MPA)，3) 联合治疗 (CEE + MPA)，或 4) 抗雌激素他莫昔芬。目的是确定激素受体表达，受体阳性细胞的位置和类型，以及对这些组织中受体表达的个体激素疗法。免疫组织化学分析将用于定位雌激素受体、孕激素受体和雄激素受体阳性细胞骨和动脉切片，并检查雄激素受体的表达乳腺和子宫组织。激素受体 mRNA 表达也会在每个组织中进行测定。结果将提供有价值的关于这些个体受体表达的新信息靶组织和不同组织特异性作用的机制激素疗法。这些研究将对绝经后妇女的健康，并将进一步定义食蟹猴猕猴被誉为女性健康的典范。