ER-BETA SELECTIVE AGONIST CORONARY PROTECTION IN MENOPAUSE

ER-β 选择性激动剂对更年期的冠状动脉保护

• 批准号: 7716373
• 负责人: R Kent HERMSMEYER
• 金额: $ 17.37万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7716373
• 关键词: Adult; Aging-Related Process; Agonist; Angiography; Blood Vessels; Breast; C-reactive protein; Cardiac Catheterization Procedures; Catheterization; Cell Proliferation; Computer Retrieval of Information on Scientific Projects Database; Coronary; Coronary artery; Dimensions; Effectiveness; Estrogen Receptor beta; Female; Fluorescence Polarization; Functional disorder; Funding; Genomics; Grant; Histopathology; Hormonal; Human; In Vitro; Incidence; Institution; Laboratories; Macaca mulatta; Measures; Menopause; Muscle Cells; Pharmaceutical Preparations; Phase; Prostate; Protocols documentation; Regulation; Research; Research Personnel; Resources; Role; Serum; Signal Transduction; Small Business Funding Mechanisms; Small Business Innovation Research Grant; Source; Steroids; Symptoms; TFPI; Testing; Thromboembolism; Thromboxane B2; United States National Institutes of Health; Urine; Vasoconstrictor Agents; Vasomotor; Woman; base; human ESR1 protein; immunocytochemistry; in vivo; indexing; male; men; normal aging; novel; prevent; receptor; response; steroid hormone

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.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 这个第二阶段的SBIR项目继续对恒河猴进行活体研究，以进一步测试一种新型的雌激素受体β(ER-β)选择性(高于ER-α)激动剂，并将其开发为人类使用的药物，该药被假设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舒缩症状。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ER-β/ER-α刺激的失衡，这种失衡伴随着性腺功能低下、更年期和正常的衰老过程。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？荧光偏振分析为该计划增加了基因组调节维度。新发现的内源性ER-β激动剂(ER-β-A)将在导管实验室的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中进行研究。新的ER-Beta-A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ER-Beta-A是否对乳腺或子宫(或男性的前列腺)细胞增殖有影响。我们将对分离的冠状动脉血管肌细胞进行研究，以探讨受体在钙离子和蛋白激酶C信号的相关保护作用中的作用。