ER beta selective agonist coronary protection-menopause

ERβ选择性激动剂冠状动脉保护-更年期

• 批准号: 6791647
• 负责人: R Kent HERMSMEYER
• 金额: $ 95.83万
• 依托单位: DIMERA, INC.
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-07 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6791647
• 关键词: Macaca mulatta; androstane compound; angiography; animal tissue; calcium ion; cardiac myocytes; chemoprevention; coronary artery; coronary disorder; drug screening /evaluation; estrogen receptors; heart disorder chemotherapy; human mortality; immunocytochemistry; nonhuman therapy evaluation; postmenopause; stimulant /agonist; thromboembolism; thromboxanes; topical drug application; vasoconstrictors

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.

描述（由申请方提供）：该II期项目继续进行恒河猴体内研究，以进一步测试并开发一种新型雌激素受体β（ER β或ER b）选择性（超过ER α或ER α）激动剂，并将其批准为人用药物，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炎症状。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刺激失衡所致，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 ERbeta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（ErbetaA或ERbA）将在导管插入实验室中在成年雌性和雄性恒河猴（Macaca mulatta）中进行研究，并在从恒河猴冠状动脉分离的VMC中进行研究。新的ER β A预防冠状动脉高反应性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。本研究将以离体冠状血管肌细胞为研究对象，探讨受体在Ca 2+和PKC信号相关保护作用中的作用。新的ER β A与PremPro（r）（口服结合马雌激素加醋酸甲羟孕酮）形成对比，后者在妇女健康倡议中未能提供心血管保护。