ER-BETA SELECTIVE AGONIST CORONARY PROTECTION IN MENOPAUSE

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 该II期SBIR项目继续对恒河猴进行体内研究，以进一步测试并开发一种新型雌激素受体β（ER-β）选择性（相对于ER-α）激动剂，该激动剂被假设可有效维持冠状动脉功能，并缓解类固醇缺乏和激素失衡的血管扩张症状，以获得批准作为人用药物。 这种新药的研制目的是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。 假设指定适应症（降低冠状动脉高反应性）是由于类固醇激素缺乏和ER-β/ER-α刺激失衡导致的，该失衡与性腺功能减退、绝经和正常衰老过程有关。 二聚体在体内心脏导管插入术和体外原代VMC（血管肌细胞）培养已经开创了有效预防高反应性的试验。 PanVera ER？荧光偏振分析为计划增加了基因组调控维度。 新发现的内源性ER-β激动剂（ER-β-A）将在成年雌性和雄性恒河猴（M。mulatta），以及从恒河猴冠状动脉分离的VMC。 新的ER-β-A在预防冠状动脉高反应性方面的有效性将通过基于血管造影术期间对血管收缩剂激发的反应的既定方案进行评估。 将测量组织因子途径抑制物（TFPI）水平，作为预防血栓栓塞的指标。 此外，血清中的C反应蛋白（CRP）和尿液中的血栓素B2将被用作不良指标。 将包括组织学和Ki 67免疫细胞化学，以确定ER-β-A是否对乳腺或子宫（或男性前列腺）细胞增殖有影响。 将研究离体冠状血管肌细胞，以研究受体在Ca 2+和PKC信号的相关保护作用中的作用。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This Phase II SBIR 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 (ER-Beta) selective (over ER-alpha) 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 ER-Beta/ER-alpha 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 ER¿ fluorescence polarization analysis adds genomic regulation dimensions to the plan. The newly discovered endogenous ER-Beta Agonist (ER-Beta-A) will be studied in adult female and male rhesus (M. mulatta) in the catheterization laboratory, and in VMC isolated from rhesus coronary arteries. The effectiveness of the new ER-Beta-A 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 ER-Beta-A 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 Ca2-plus and PKC signals.