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

衰老和细胞衰老在颅内动脉瘤破裂发展中的作用

• 批准号: 10680060
• 负责人: SATORU EGUCHI
• 金额: $ 60.9万
• 依托单位: ST. JOSEPH'S HOSPITAL AND MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10680060
• 关键词: Affect; Aging; Aneurysm; Aneurysmal Subarachnoid Hemorrhages; Biological; Biological Process; Cardiovascular Diseases; Cell Aging; Cell Survival; Cell secretion; Cells; Cellular Stress; Chronology; Clinical; Clinical Research; Data; Development; Event; Exposure to; Future; Homeostasis; Human; In Vitro; Individual; Inflammation; Inflammatory; Intracranial Aneurysm; Laboratories; Link; Mediating; Modeling; Mus; Pathologic; Patients; Pharmaceutical Preparations; Phenotype; Prevention; Procedures; Proteomics; Reactive Oxygen Species; Risk; Risk Factors; Role; Rupture; Ruptured Aneurysm; Severities; Sex Differences; Stress; Subarachnoid Hemorrhage; Surgical Clips; Testing; Tissues; Transgenes; adverse outcome; age effect; age related; aged; cell type; cerebral artery; cytokine; disorder control; experimental study; hemodynamics; in vivo; interest; mitochondrial dysfunction; mortality; new therapeutic target; paracrine; pharmacologic; pre-clinical; preclinical study; premature; prevent; screening; senescence; sex; targeted treatment; tissue repair; young adult

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.

项目概要 临床研究一致表明，衰老与颅内肿瘤风险增加之间存在密切关联。 动脉瘤破裂传统上被认为是不可改变的危险因素。 越来越明显的是，与衰老相关的一些生物变化是可以改变或部分改变的 因此，针对年龄相关生物事件的药物疗法可用于预防。 动脉瘤破裂。 衰老会引起细胞稳态的多种变化，衰老的标志之一是细胞衰老。 永久增殖停滞状态。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) 除了衰老之外， 由炎症、活性氧、线粒体功能障碍引起的细胞应激 血流动力学压力会导致年轻人和老年人“过早的病理性衰老”。 我们追寻的是由年龄相关和早产引起的过度衰老细胞负担 衰老可能通过 SASP 诱导的炎症、组织重塑和 我们将测试消除衰老细胞是否可以防止动脉瘤破裂。 此外，我们将使用蛋白质组学方法鉴定促进破裂的 SASP 谱。 目标 1 是测试衰老是否会促进动脉瘤破裂，同时增加总衰老细胞负担。 使用动脉瘤小鼠，我们将建立衰老与促进动脉瘤破裂之间的联系 我们还将评估衰老的潜在性别差异及其对动脉瘤的影响。 目标 2 是测试细胞衰老是否会促进动脉瘤破裂。 和转基因介导的“衰老”方法来建立细胞衰老和衰老之间的因果关系 我们将采用 (2a) 一种典型的抗衰老药物 ABT263 和 (2b) 转基因介导的药物。 此外，我们将评估年龄相关的相对贡献。 目标 3 是确定促进破裂的 SASP 谱。 并建立未来研究的筛选平台 3a。 目标 1 和 2，我们将确定促进破裂的 SASP 谱 3b。 使用 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 我们将验证筛选平台和密钥。 促进破裂的 SASP。 该提案旨在建立衰老、衰老和动脉瘤破裂之间的因果关系。 本提案中开发的筛选平台将用于测试现有的 senolytics 和 senomorphs 在未来的研究中预防动脉瘤破裂。