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，衰老与增加颅内疾病的风险之间有很强的相关性。 动脉瘤破裂。传统上，老龄化被认为是一个不可改变的风险因素。然而，它是 越来越明显的是，与衰老相关的一些生物变化可以改变或部分改变 可逆的。因此，可以利用针对年龄相关生物事件的药物疗法来预防 动脉瘤破裂。 衰老会引起细胞内环境平衡的各种变化。衰老的标志之一是细胞衰老，一种 永久停止扩散的状态。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)。除了老化， 炎症、活性氧、线粒体功能障碍引起的细胞应激 血液动力学应激对年轻人和老年人都会导致“过早的、病理性衰老”。因此， 我们假设过度衰老的细胞负担共同由年龄相关和早产引起 衰老可能通过SASP诱导的炎症、组织重塑和 组织损伤。我们将测试消除衰老细胞是否可以防止动脉瘤破裂。在……里面 此外，我们将使用蛋白质组学方法鉴定促进SASP破裂的图谱。 目的1是测试衰老是否促进了动脉瘤破裂，同时增加了总的衰老细胞负荷。 利用动脉瘤的小鼠，我们将建立衰老和促进动脉瘤破裂之间的联系。 两性都有。我们还将评估衰老过程中潜在的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。我们利用药理作用 转基因介导的“衰老”方法来建立细胞衰老和细胞衰老之间的因果联系 动脉瘤破裂。我们将使用(2a)典型的敏感药物ABT263和(2b)转基因介导的 P16-3MR小鼠的感受器裂解。此外，我们将评估与年龄相关的 衰老和应激诱导的早衰。目标3是确定促进SASP破裂的特征 并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，我们将确定一个促进破裂的SASP简档。3B.我们将确定产生的细胞类型 促进破裂的SASP。使用来自3a和3b的数据，我们将建立一个从体外到体内的筛查。 用于测试现有感光物质和感光物质的平台。3C。我们将验证筛查平台和密钥 促进破裂的SASP。 这项建议旨在确定衰老、衰老和动脉瘤破裂之间的因果联系。这个 本方案中开发的筛选平台将用于测试现有的感受器和感受器 在未来的研究中预防动脉瘤破裂。

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.