Does Senescence Impair the Cardiovascular Benefits of Menopause Hormone Therapy?

衰老是否会损害更年期激素疗法对心血管的益处？

• 批准号: 10429132
• 负责人: Lin Zhu
• 金额: $ 12.02万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10429132
• 关键词: Academic Medical Centers; Aftercare; Aging; Animal Model; Arterial Fatty Streak; Arteries; Atherosclerosis; Blood; Bone Marrow; Bone Marrow Transplantation; Cardiovascular system; Cell Aging; Cell physiology; Cells; Cessation of life; Clinical; Clinical Trials; Competence; Data; Development Plans; Diet; Drops; Dyslipidemias; Endothelium; Estradiol; Estrogens; Event; Faculty; Female; Functional disorder; Goals; Gonadal Steroid Hormones; Homeostasis; Hyperlipidemia; Immune; Immunofluorescence Immunologic; Impairment; In Vitro; Individual; Inflammation; Inflammatory; Insulin; Interferon Type II; Interferons; Knowledge; Lead; Leadership; Lesion; Lipids; Liver; Mediating; Menopause; Mentorship; Metabolic; Methods; Mus; Operative Surgical Procedures; Ovariectomy; Ovary; Paper; Pathway interactions; Physicians; Physiology; Positioning Attribute; Postmenopause; Premenopause; Prevention; Publishing; Regulation; Reporting; Research; Research Design; Research Personnel; Resolution; Risk; Role; Scientist; Sex Differences; Signal Transduction; Stains; Surgical Models; Techniques; Testing; Therapeutic; Training; Translational Research; Transplantation; Woman; aged; blood lipid; cardiovascular disorder risk; career; career development; design; experience; feeding; hormone therapy; improved; in vivo; indexing; lipid metabolism; men; mouse model; novel; older women; prevent; reconstitution; repaired; senescence; skills; skills training; stem cells; tenure track; western diet; young woman

Does Senescence Impair the Cardiovascular Benefits of Menopause Hormone Therapy? Atherosclerotic cardiovascular disease (ASCVD) causes approximately one-third of all deaths worldwide. The protection in women against ASCVD is reduced with aging and menopause. Menopausal hormone therapy (MHT) has not replicated this protection in postmenopausal women in clinical trials, highlighting the gap in our knowledge of the mechanisms of the protecting roles of estrogens in young women and impaired protection of MHT in aged women. The goal of this application is to investigate the mechanism by which MHT fails to reduce ASCVD events despite metabolic improvements and to define a therapeutic approach to reduce ASCVD risk in aged women. To recapitulate the physiology in postmenopausal women with MHT, mouse models of estradiol (E2) treatment with surgical menopause and atherosclerosis regression have been designed. Preliminary studies show that atherosclerosis burden under MHT was associated with blood inflammatory factor interferon gamma (IFNg) levels when hyperlipidemia was reduced. These results mirror the clinical observation that MHT could not improve postmenopausal ASCVD risk when the inflammation index is high. Aging and senescence-related cellular dysfunction may drive inflammation in the artery wall even when the blood lipid profile is normal. My overarching hypothesis is that inflammation resolution in atherosclerotic lesions is impaired by senescence-related incompetence of arterial repair in postmenopausal women with MHT. I propose that ASCVD risk will be reduced with MHT when lipid risks and inflammation in atherosclerotic lesions are resolved. I will explore this hypothesis with two Specific Aims: 1) Test the hypothesis that MHT improves lipid metabolism but does not resolve arterial senescence and atherosclerotic inflammation. 2) Test the hypothesis that correcting senescence and limiting inflammation in atherosclerotic lesions will restore the cardiovascular benefits of menopause E2 treatment. Studies proposed in this application will reveal critical mechanisms underlying why MHT fails to reverse atherosclerosis and lead to therapeutic approaches to reduce ASCVD risk in postmenopausal women. My career goal is to lead a research team focused on managing ASCVD risks. I have a strong background in lipid research and in the atherosclerosis field. The proposed project will afford me new expertise in 1) studying cellular senescence and immune cell functions in inflammation resolution in atherosclerosis regression, 2) translational science to reduce ASCVD risk by developing therapeutic methods to block inflammation in the artery wall. I have proposed a career development plan that integrates formal didactic training with a diverse hands-on mentorship committee to further refine my skills, competences, and leadership ability. It is anticipated that completion of the proposed project and training plan will place me in an ideal position to receive a tenure track faculty position.

衰老会损害更年期激素治疗的心血管益处吗？ 动脉粥样硬化心血管疾病（ASCVD）造成所有死亡的三分之一 全世界。随着衰老和更年期，妇女免受ASCVD的保护。更年期 激素治疗（MHT）在临床试验中没有复制这种绝经后妇女的保护， 强调了我们了解雌激素在年轻女性中保护作用机制的差距 以及对年龄妇女的MHT保护受损。 该应用的目的是研究MHT无法减少ASCVD的机制 事件尽管有代谢改善，并定义了一种治疗方法，以降低老年人的ASCVD风险 女性。为了概括具有MHT的绝经后妇女的生理学，雌二醇的小鼠模型（E2） 已经设计了手术更年期和动脉粥样硬化消退的治疗。初步研究 表明MHT下的动脉粥样硬化负担与血液炎症因子干扰素有关 降低高脂血症时γ（IFNG）水平。这些结果反映了临床观察结果 当炎症指数高时，MHT无法改善绝经后ASCVD风险。老化和 与衰老相关的细胞功能障碍也可能驱动动脉壁的炎症，即使是血脂 配置文件是正常的。我的总体假设是，动脉粥样硬化病变中的炎症是 MHT绝经后妇女中动脉修复与衰老相关的无能受损。我 提出，当脂质风险和动脉粥样硬化病变中的脂质风险和炎症时，ASCVD风险将降低 解决。我将以两个具体的目的探讨这一假设：1）检验MHT改善的假设 脂质代谢，但不能解决动脉衰老和动脉粥样硬化炎症。 2）测试 假设在动脉粥样硬化病变中纠正衰老和限制炎症将恢复 更年期E2治疗的心血管益处。该应用中提出的研究将揭示关键 为什么MHT无法逆转动脉粥样硬化并导致治疗方法的基础机制 减少绝经后妇女的ASCVD风险。 我的职业目标是领导专注于管理ASCVD风险的研究团队。我很强 脂质研究和动脉粥样硬化领域的背景。拟议的项目将给我带来新的作用 1）研究细胞衰老和免疫细胞功能的炎症解决方案 动脉粥样硬化回归，2）转化科学通过开发治疗方法来降低ASCVD风险 阻止动脉壁中的炎症。我提出了一项职业发展计划，以整合正式 与各种动手指导委员会的教学培训，以进一步完善我的技能，能力和 领导能力。预计拟议项目和培训计划的完成将使我进入 获得任期教师职位的理想位置。