Does Senescence Impair the Cardiovascular Benefits of Menopause Hormone Therapy?

衰老是否会损害更年期激素治疗的心血管益处？ 动脉粥样硬化性心血管疾病（ASCVD）导致约三分之一的死亡 国际吧女性对ASCVD的保护随着年龄的增长和绝经而减少。更年期 激素治疗（MHT）在临床试验中没有在绝经后妇女中复制这种保护作用， 强调我们对雌激素在年轻女性中的保护作用机制的认识存在差距 老年妇女MHT保护受损。 本申请的目的是研究MHT未能降低ASCVD的机制 尽管代谢改善，但仍发生ASCVD事件，并确定降低老年人ASCVD风险的治疗方法。 妇女为了概括患有MHT的绝经后妇女的生理学， 已经设计了手术绝经和动脉粥样硬化消退的治疗。初步研究 表明MHT下动脉粥样硬化负荷与血液炎症因子干扰素相关 γ（IFNg）水平时，高脂血症降低。这些结果反映了临床观察， 当炎症指数高时，MHT不能改善绝经后ASCVD的风险。老化和 衰老相关的细胞功能障碍可能会导致动脉壁炎症， 侧写正常。我的首要假设是，动脉粥样硬化病变的炎症消退是 绝经后MHT妇女中衰老相关动脉修复不全的损害。我 提出当动脉粥样硬化病变中的脂质风险和炎症时， 都解决了我将通过两个具体的目的来探讨这个假设：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动脉粥样硬化的发生， 更年期E2治疗的心血管益处。本申请中提出的研究将揭示关键的 MHT不能逆转动脉粥样硬化并导致治疗方法的潜在机制 降低绝经后妇女的ASCVD风险。 我的职业目标是领导一个专注于管理ASCVD风险的研究团队。我有一种强烈 脂质研究和动脉粥样硬化领域的背景。该项目将为我提供新的 专长1）研究细胞衰老和免疫细胞在炎症消退中的功能， 动脉粥样硬化消退，2）通过开发治疗方法降低ASCVD风险的转化科学 来阻止动脉壁的炎症我提出了一个职业发展计划， 教学培训与多样化的实践指导委员会，以进一步完善我的技能，能力， 领导能力。预计完成拟议的项目和培训计划后，我将在 获得终身教职的理想职位。

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.