Does Senescence Impair the Cardiovascular Benefits of Menopause Hormone Therapy?

衰老是否会损害更年期激素治疗对心血管的益处？ 动脉粥样硬化性心血管疾病(ASCVD)导致的死亡约占所有死亡人数的三分之一 全世界。随着年龄的增长和绝经，女性对ASCVD的保护作用会减弱。更年期 激素疗法(MHT)在临床试验中并未在绝经后妇女中复制这种保护作用， 突出了我们对雌激素在年轻女性中的保护作用机制的认识上的差距 老年女性对MHT的保护作用减弱。 该应用程序的目标是研究MHT未能减少ASCVD的机制 尽管新陈代谢有所改善，但仍发生了一些事件，并确定了一种降低老年人ASCVD风险的治疗方法 女人。为了概述绝经后女性MHT的生理学，雌二醇(E_2)的小鼠模型 已经设计了手术绝经和动脉粥样硬化消退的治疗方法。初步研究 提示MHT下动脉粥样硬化负荷与血炎性因子干扰素有关 高脂血症降低时的γ(IFNG)水平。这些结果反映了临床观察 当炎症指数较高时，MHT不能改善绝经后ASCVD的风险。老龄化和 衰老相关的细胞功能障碍可能会导致动脉壁炎症，即使当血脂 个人资料正常。我的主要假设是动脉粥样硬化病变中的炎症消退是 绝经后MHT女性因衰老相关的动脉修复能力不足而受损。我 当动脉粥样硬化病变中的脂质风险和炎症时，MHT将降低ASCVD的风险 都被解决了。我将带着两个具体的目的来探讨这个假设：1)测试MHT改善的假设 脂代谢，但不能解决动脉衰老和动脉粥样硬化性炎症。2)测试 假设纠正动脉粥样硬化病变的衰老和限制炎症将恢复 更年期雌激素治疗对心血管的益处。在本申请中提出的研究将揭示关键的 MHT未能逆转动脉粥样硬化并导致治疗方法的机制 降低绝经后妇女患ASCVD的风险。 我的职业目标是领导一个专注于管理ASCVD风险的研究团队。我有一个很强的 脂类研究和动脉粥样硬化领域的背景。拟议中的项目将给我带来新的机会 擅长1)研究细胞衰老和免疫细胞功能在炎症消退中的作用 动脉粥样硬化回归，2)通过开发治疗方法来降低ASCVD风险的转化科学 来阻止动脉壁的炎症。我已经提出了一项职业发展计划，将正式的 与不同的实践指导委员会一起进行教学培训，以进一步完善我的技能、能力和 领导能力。预计拟议的项目和培训计划的完成将使我处于 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.