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: 10612102
• 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/10612102
• 关键词: Academic Medical Centers; 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; Disease Progression; 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; Leadership; Lesion; Lipids; Liver; Mediating; Menopause; Mentorship; Metabolic; Methods; Mus; Ovariectomy; Ovary; Paper; Pathway interactions; Physicians; Physiology; Positioning Attribute; Postmenopause; Premenopause; Prevention; Publishing; Regulation; Reporting; Research; Research Design; Research Personnel; Resolution; Risk; Role; Safe Sex; Scientist; Sex Differences; Signal Transduction; Stains; 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; menopausal hormone therapy; mouse model; novel; older women; prevent; reconstitution; repaired; senescence; skills; stem cells; surgical menopause; 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.

衰老是否会损害更年期激素疗法对心血管的益处？ 动脉粥样硬化性心血管疾病 (ASCVD) 导致约三分之一的死亡 全世界。随着年龄的增长和更年期，女性对 ASCVD 的保护作用会减弱。更年期 在临床试验中，激素疗法 (MHT) 尚未在绝经后妇女中复制这种保护作用， 强调我们对年轻女性雌激素保护作用机制的了解存在差距 老年女性 MHT 的保护作用受损。 本申请的目标是研究 MHT 未能减少 ASCVD 的机制 尽管代谢有所改善，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 女性。为了重现患有 MHT 的绝经后妇女的生理学，雌二醇 (E2) 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 表明 MHT 下的动脉粥样硬化负荷与血液炎症因子干扰素相关 高脂血症降低时γ (IFNg) 水平。这些结果反映了临床观察： 当炎症指数较高时，MHT 无法改善绝经后 ASCVD 风险。老化和 即使血脂水平升高，与衰老相关的细胞功能障碍也可能导致动脉壁炎症 个人资料正常。我的首要假设是动脉粥样硬化病变中的炎症消退是 患有 MHT 的绝经后妇女因衰老相关的动脉修复功能不全而受损。我 提出当动脉粥样硬化病变存在脂质风险和炎症时，MHT 可以降低 ASCVD 风险 已解决。我将通过两个具体目标来探索这个假设：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 假设纠正衰老和限制动脉粥样硬化病变中的炎症将恢复 更年期 E2 治疗对心血管的益处。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潜在机制 降低绝经后妇女 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。我有很强的 脂质研究和动脉粥样硬化领域的背景。拟议的项目将为我提供新的 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 阻止动脉壁炎症。我提出了一个职业发展计划，其中整合了正式的 与多元化的实践指导委员会一起进行教学培训，以进一步提高我的技能、能力和 领导能力。预计完成拟议的项目和培训计划将使我能够 获得终身教职的理想职位。