ER beta selective agonist coronary protection-menopause

描述（由申请人提供）：该II期项目继续在猕猴体内进行研究，以进一步测试并开发一种新型雌激素受体β （erβ或ERb）选择性（优于erα或ERa）激动剂，该激动剂被认为可有效维持冠状动脉功能，并可缓解类固醇缺乏和激素失衡的血管舒张症状。这种新药的研制目的是保护冠状动脉不受过度反应的影响，作为减少男性和女性冠状动脉功能障碍发生率的积极措施。指定的适应症是减少冠状动脉高反应性，假设是由于类固醇激素缺乏和erβ / erα刺激失衡导致的，这些失衡与性腺功能减退、更年期和正常衰老过程有关。二聚体体内心导管和体外原代VMC（血管肌细胞）培养率先进行了预防过度反应性的有效性试验。PanVera ERbeta荧光偏振分析增加了基因组调控的维度。新发现的内源性ERbeta激动剂（ErbetaA或ERbA）将在导管实验室对成年雌性和雄性恒河猴（Macaca mulatta）以及从恒河猴冠状动脉分离的VMC进行研究。新的ERbetaA在预防冠状动脉高反应性方面的有效性将通过一个基于血管造影期间血管收缩剂挑战反应的既定方案来评估。组织因子途径抑制剂（TFPI）水平将被测量为防止血栓栓塞的一个指标。此外，血清c反应蛋白（CRP）和尿液血栓素B2将作为不良指标。将包括组织病理学和Ki67免疫细胞化学来确定ERbetaA是否对乳腺或子宫（或男性前列腺）细胞增殖有影响。将研究分离的冠状动脉血管肌细胞，以研究受体在ca2 +和PKC信号的相关保护作用中的作用。新的ERbetaA将与PremPro（口服结合马雌激素加醋酸甲孕酮）进行对比，后者在妇女健康倡议中未能提供心血管保护。

DESCRIPTION (provided by applicant): This Phase II project continues with studies of rhesus monkeys in vivo to further test, and develop toward approval as a drug for human use, a novel estrogen receptor beta (ERbeta or ERb) selective (over ERalpha or ERa) agonist that is hypothesized to be effective for maintaining function of coronary arteries and also for relieving vasomotor symptoms of steroid deficiency and hormonal imbalance. The new drug will be formulated with the aim of protection of coronary arteries against hyperreactivity as a proactive step to reduce the incidence of coronary dysfunction in both women and men. The designated indication, to reduce coronary hyperreactivity, is hypothesized to result from deficiencies in steroid hormones and the imbalance of ERbeta/ERalpha stimulation that develops with hypogonadal function, menopause, and in the normal aging process. Dimera in vivo cardiac catheterization and in vitro primary VMC (vascular muscle cell) cultures have pioneered tests for effectiveness in preventing hyperreactivity. PanVera ERbeta fluorescence polarization analysis adds genomic regulation dimensions to the plan. The newly discovered endogenous ERbeta Agonist (ErbetaA or ERbA) will be studied in adult female and male rhesus (Macaca mulatta) in the catheterization laboratory, and in VMC isolated from rhesus coronary arteries. The effectiveness of the new ERbetaA in preventing coronary hyperreactivity will be assessed by an established protocol based on responses to vasoconstrictor challenges during angiography. Tissue Factor Pathway Inhibitor (TFPI) levels will be measured as an index of protection against thromboembolism. In addition, C-Reactive Protein (CRP) in serum and thromboxane B2 in urine will be used as adverse indicators. Histopathology and Ki67 immunocytochemistry will be included to determine whether there are effects of the ERbetaA on breast or uterine (or prostate in males) cell proliferation. Isolated coronary vascular muscle cells will be studied to investigate receptor roles in related protective actions on Ca 2+and PKC signals. The new ERbetaA is to be contrasted with PremPro(r) (oral conjugated equine estrogens plus medroxyprogesterone acetate) which failed to provide cardiovascular protection in the Women's Health Initiative.