Roles of aging and cellular senescence in the development of intracranial aneurysm rupture

项目摘要 临床研究一直表明，衰老与颅内动脉瘤风险增加之间存在密切联系。 动脉瘤破裂衰老传统上被认为是一个不可改变的风险因素。但据 越来越明显的是，一些与衰老相关的生物学变化是可以改变的， 可逆的因此，靶向年龄相关生物学事件的药理学疗法可用于预防 子宫破裂。 衰老诱导细胞内稳态的各种变化。衰老的标志之一是细胞衰老， 永久性增殖停滞状态。衰老细胞分泌促炎和组织重塑 细胞因子统称为“衰老相关分泌表型”（SASP）。除了衰老， 由炎症、活性氧、线粒体功能障碍和 血液动力学应激在年轻和老年个体中均引起“过早的病理性衰老”。因此，在本发明中， 我们假设，过度衰老细胞负担共同造成的年龄相关的和过早的， 衰老可能通过SASP诱导的炎症、组织重塑和 组织损伤我们将测试衰老细胞的清除是否能防止囊肿破裂。在 此外，我们将使用蛋白质组学方法鉴定促进破裂的SASP谱。 目的1是测试老化是否促进动脉瘤破裂，同时增加总衰老细胞负荷。 使用一只动脉瘤小鼠，我们将建立衰老与动脉瘤破裂之间的联系， 男女都有。我们还将评估衰老的潜在性别差异及其对动脉瘤的影响 破裂目的2是测试细胞衰老是否促进动脉瘤破裂。我们利用药理学 和转基因介导的“衰老清除”方法，以建立细胞衰老和 动脉瘤破裂我们将采用（2a）原型衰老清除药物ABT 263和（2b）转基因介导的抗衰老药物ABT 263。 p16- 3 MR小鼠的衰老。此外，我们将评估年龄相关的 衰老和应激诱导的早衰。目的3是鉴定促破裂SASP谱 为今后的研究建立筛选平台。3a.通过将蛋白质组学应用于脑动脉， 目标1和2，我们将确定一个破裂促进SASP配置文件。3b.我们将鉴定出产生 促进SASP破裂。使用来自3a和3b的数据，我们将建立“体外到体内”筛选 用于测试现有senolytics和senomorphs的平台。3c.我们将验证筛选平台和密钥 促进SASP破裂。 该提案旨在建立衰老、衰老和子宫内膜破裂之间的因果关系。的 本提案中开发的筛选平台将用于测试现有的senolytics和senomorphs， 在未来的研究中防止子宫破裂。

Project Summary Clinical studies have consistently shown a strong association between aging and increased risk for intracranial aneurysm rupture. Aging has traditionally been considered a non-modifiable risk factor. However, it is becoming evident that some of the biological changes associated with aging can be modifiable or partially reversible. Thus, pharmacological therapies targeting age-related biological events may be utilized to prevent aneurysmal rupture. Aging induces diverse changes in cellular homeostasis. One of the hallmarks of aging is cellular senescence, a state of permanent proliferative arrest. Senescent cells secrete pro-inflammatory and tissue remodeling cytokines collectively called the "Senescence-Associated Secretory Phenotype" (SASP). In addition to aging, cellular stresses induced by inflammation, reactive oxygen species, mitochondrial dysfunction, and hemodynamic stresses cause "premature, pathological senescence" in both young and aged individuals. Thus, we hypothesize that excessive senescent cell burden collectively caused by age-related and premature senescence may promote aneurysmal rupture through SASP-induced inflammation, tissue remodeling, and tissue damage. We will test whether the elimination of senescent cells prevents aneurysmal rupture. In addition, we will identify a rupture-promoting SASP profile using a proteomic approach. Aim 1 is to test whether aging promotes aneurysm rupture while increasing the total senescent cell burden. Using a mouse of aneurysm, we will establish the link between aging and the promotion of aneurysm rupture in both sexes. We will also assess potential sex differences in senescence and their contributions to aneurysm rupture. Aim 2 is to test whether cellular senescence promotes aneurysm rupture. We utilize pharmacological and transgene-mediated “senolytic” approaches to establish the causal link between cellular senescence and aneurysm rupture. We will employ (2a) a prototypical senolytic drug, ABT263 and (2b) transgene-mediated senolysis of p16-3MR mice. In addition, we will assess the relative contribution between age-related senescence and stress-induced premature senescence. Aim 3 is to identify rupture-promoting SASP profile and establish a screening platform for future studies. 3a. By applying proteomics to the cerebral arteries from Aims 1 and 2, we will identify a rupture-promoting SASP profile. 3b. We will identify the cell type that produces rupture-promoting SASPs. Using the data from 3a and 3b, we will establish an "in vitro to in vivo" screening platform for testing existing senolytics and senomorphs. 3c. We will validate the screening platform and key rupture-promoting SASPs. This proposal seeks to establish the causal links between aging, senescence, and aneurysmal rupture. The screening platform developed in this proposal will be used to test existing senolytics and senomorphs for preventing aneurysmal rupture in future studies.