ER beta selective agonist coronary protection-menopause

描述(申请人提供)：这个第二阶段的项目继续在体内对恒河猴进行研究，以进一步测试一种新型的雌激素受体β(ERbeta或ERb)选择性(超过ERpha或ERa)激动剂，假设它可以有效地维持冠状动脉功能，并缓解类固醇缺乏和激素失衡的血管运动症状，并将其开发为人类使用的药物，并朝着批准的方向发展。这种新药的配方将旨在保护冠状动脉免受高反应性的影响，作为减少女性和男性冠状动脉功能障碍发生率的积极步骤。被指定的适应症是为了减少冠状动脉的高反应性，假设是由于类固醇激素的缺乏和随着性腺功能低下、更年期和正常衰老过程而发展的ERbeta/ERpha刺激的失衡。DiMera体内心脏导管术和体外原代VMC(血管肌肉细胞)培养已经率先测试了预防高反应性的有效性。PanVera ERbeta荧光偏振分析为该计划增加了基因组调控维度。新发现的内源性ERbeta激动剂(ErbetaA或Erba)将在导管室的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中进行研究。新的ERbetaA在预防冠状动脉高反应性方面的有效性将通过在血管造影术期间对血管收缩挑战的反应的既定方案来评估。组织因子途径抑制物(TFPI)水平将作为预防血栓栓塞症的一个指标。此外，血清C反应蛋白(CRP)和尿中血栓素B2(TXB2)将作为不良指标。将包括组织病理学和Ki67免疫细胞化学，以确定ERbetaA是否对乳腺或子宫(或男性的前列腺)细胞增殖有影响。我们将对分离的冠脉血管肌细胞进行研究，以探讨受体在钙和蛋白激酶C信号的相关保护作用中的作用。新的ERbetaA将与Prempro(R)(口服结合马类雌激素和甲羟孕酮醋酸酯)形成对比，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.