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; 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.

项目摘要 临床研究一直表明，衰老与颅内风险增加之间有很强的关联 动脉瘤破裂。传统上，衰老被认为是不可修改的危险因素。但是，是 成为证据表明，与衰老相关的某些生物学变化可能是可修改的或部分的 可逆。这是针对年龄相关生物事件的药物疗法可用于防止 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感应，a 永久性逮捕的状态。衰老细胞秘密促炎和组织重塑 细胞因子统称为“衰老相关的秘书表型”（SASP）。除了衰老， 炎症，活性氧，线粒体功能障碍和 血液动力学应力导致年轻人和老年人的“过早，病理感应”。那， 我们假设超过年龄相关和过早引起的超级感觉细胞伯嫩伯嫩 感应可以通过SASP诱导的注射，组织重塑和 组织损伤。我们将测试消除感觉细胞是否可以防止动脉瘤破裂。在 此外，我们将使用蛋白质组学方法确定促进破裂的SASP曲线。 AIM 1是测试衰老是否促进动脉瘤破裂，同时增加总感觉细胞负担。 使用动脉瘤的小鼠，我们将建立衰老与促进动脉瘤破裂之间的联系 两个性别。我们还将评估感受的潜在性别差异及其对动脉瘤的贡献 破裂。 AIM 2是测试细胞感应是否促进动脉瘤破裂。我们利用药理 并翻译介导的“鼻溶剂”方法，以建立细胞感应和 动脉瘤破裂。我们将采用（2a）一种典型的鼻溶剂，ABT263和（2B）转基因介导的 P16-3MR小鼠的鼻溶。此外，我们将评估与年龄相关的相对贡献 感应和应力诱导的过早感应。 AIM 3是识别促进破裂的SASP轮廓 并建立一个未来研究的筛选平台。 3a。通过将蛋白质组学应用于大脑动脉 目标1和2，我们将确定促进破裂的SASP曲线。 3b。我们将确定产生的单元格类型 破裂的SASP。使用来自3A和3B的数据，我们将建立“体内的体外”筛选 测试现有的鼻溶剂和鼻孔的平台。 3C。我们将验证筛选平台和密钥 破裂的SASP。 该提案旨在建立衰老，感应和动脉瘤破裂之间的因果关系。 该提案中开发的筛选平台将用于测试现有的鼻孔和鼻孔词 在未来的研究中防止动脉瘤破裂。