Role of cellular senescence in cardiovascular aging

项目总结 老龄化是心血管疾病(CVD)的主要风险因素，到2030年，40%的美国人将 患有某种形式的脑血管病，给社会带来巨大的经济损失。尽管在治疗心血管疾病方面取得了显著进展 在过去的几十年里，关于心血管功能障碍为什么会随着年龄的增长而增加，我们仍然知之甚少。一 心血管衰老的潜在原因是细胞衰老。这种复杂的应激反应可能是有益的 或有害的，取决于生理环境。回应的两个特点是：1)永久逮捕 细胞增殖，在基因毒性的侮辱下防止癌症的发展；2)发展一种 衰老相关分泌表型(SASP)--转录上调和分泌 大量的炎性细胞因子、趋化因子、生长因子和蛋白酶。衰老细胞随时间延长而增加 年龄，包括在心血管(CV)系统中，SASP与各种年龄相关的 病理，包括心脏和血管功能障碍。随着年龄的增长，衰老的细胞会在心脏和 小鼠和人类的血管系统，但尚不清楚细胞衰老是导致还是导致 心血管老化。我们开发了一种新的小鼠模型，它允许可视化和消除 体内衰老细胞及其从组织中分离，使研究整合的功能成为可能 系统--如心脏和血管系统--有或没有衰老细胞。我们打算测试一下这部小说 假设衰老细胞，特别是SASP，是一个重要的机械性过程驱动 简历老化。为了验证这一假设，我们将制定三个具体目标。 目的1：心血管系统衰老的体内后果。这一目标将决定何时以及 其中衰老细胞出现在心血管系统中，使用急性模型，以及自然衰老的小鼠。我们 将采用我们的新型小鼠模型，即3MR小鼠，在该模型中，我们可以消除细胞以对比CV功能 没有衰老细胞；目标2：衰老细胞在调节心脏和动脉功能中的作用。 这一目标将决定CV中不同类型的细胞对衰老的敏感性，包括心肌细胞， 从两条动脉和完整心脏分离的血管内皮细胞和血管平滑肌细胞。我们会 确定衰老细胞的分泌因子如何影响其他类型细胞的功能 遗传策略；目标3：目标1-2中确定的衰老标记的翻译验证。拥有 建立了不同细胞类型因衰老而产生的特定蛋白质和基因表达特征 目标1和目标2，在这个最终目标中，我们将使用一种新的翻译模型--人类内皮细胞的活组织检查 来验证我们关于不同年龄人类衰老的预测。 总体而言，我们的计划将为衰老作为年龄的主要调节因素的作用提供新的见解- 相关的心血管疾病，并可能提供新的机会目标，以抗击这一毁灭性的疾病。

PROJECT SUMMARY Aging is the primary risk factor for cardiovascular disease (CVD), and by 2030, 40% of Americans will have some form of CVD incurring a huge economic toll on society. Despite significant gains in treating CVD over the last few decades, much remains unknown about why cardiovascular dysfunction increases with age. One potential cause of cardiovascular aging is cellular senescence. This complex stress response can be beneficial or detrimental, depending on the physiological context. Two hallmarks of the response are: 1) a permanent arrest of cell proliferation, preventing development of cancer in the face of genotoxic insults; 2) development of a senescence-associated secretory phenotype (SASP) -- the transcriptional upregulation and secretion of numerous inflammatory cytokines, chemokines, growth factors and proteases. Senescent cells increase with age, including in the cardiovascular (CV) system, and the SASP is associated with a variety of age-related pathologies, including cardiac and vascular dysfunction. Senescent cells accumulate with age in the hearts and vasculature of mice and humans, but it is not known if cellular senescence is a cause or consequence of cardiovascular aging. We developed a novel mouse model that permits the visualization and elimination of senescent cells in vivo and their isolation from tissues, making it possible to study the function of integrated systems -- such as the heart and vasculature -- with and without senescent cells. We propose to test the novel hypothesis that senescent cells, and particularly the SASP, are an important mechanistic process driving CV aging. To test this hypothesis, we will develop three specific aims. Aim 1: In vivo consequences of senescence in the CV system. This aim will determine when and where senescent cells arise in the cardiovasculature, using an acute model, as well as naturally aged mice. We will employ our novel mouse model, the 3MR mouse in which we can eliminate cells to contrast CV function with and without senescent cells; Aim 2: Role of senescent cells in modulating cardiac and arterial function. This aim will determine the sensitivity of different cell types in the CV to senescence, including cardiomyocytes, endothelial cells, and vascular smooth muscle cells isolated from both arteries and intact hearts. We will determine how secreted factors from senescent cells influence function of other cell types using co-cultures and genetic strategies; Aim 3: Translational validation of senescent markers identified in Aims 1-2. Having established specific protein and gene expression signatures for different cell types as a result of senescence in aims 1 and 2, in this final aim we will use a novel translational model – biopsies of endothelial cells from humans to validate our predictions about senescence in different aged humans. Overall our program will provide novel insights into the role of senescence as a major mediator of age- related CVD, and potentially provide new targets of opportunity to combat this devastating disorder.