The Role of Cellular Senescence in Atherosclerosis

细胞衰老在动脉粥样硬化中的作用

• 批准号: 9044285
• 负责人: Bennett G Childs
• 金额: $ 3.38万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2017-04-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9044285
• 关键词: Address; Arterial Fatty Streak; Arteries; Atherosclerosis; Attenuated; Benign; Biology; Blood; Cardiovascular Diseases; Cell Aging; Cells; Chemotactic Factors; Chemotaxis; Chronic Disease; Conceptions; Cultured Cells; Data; Deposition; Detection; Development; Disease; Disease model; Emigrations; Endothelial Cells; Enzymes; Excision; Exposure to; Extracellular Matrix; Extracellular Matrix Degradation; Flow Cytometry; Functional disorder; Ganciclovir; Goals; Growth; High Fat Diet; Human; Immune; Immunofluorescence Immunologic; In Situ; Incidence; Infiltration; Inflammation; Inflammatory; Interleukins; Intervention; Knockout Mice; Knowledge; Lesion; Lipids; Low Density Lipoprotein Receptor; Methods; Modeling; Monitor; Morbidity - disease rate; Mus; Myopathy; Organ; Patients; Peptide Hydrolases; Pharmaceutical Preparations; Phenotype; Process; Production; Property; Reporter; Research; Role; Rupture; Senile Plaques; Serum; Smooth Muscle; Smooth Muscle Myocytes; Source; Staging; Staining method; Stains; Testing; Therapeutic Intervention; Time; Transgenes; Transgenic Organisms; Transplantation; Vascular Smooth Muscle; Work; age related; atherogenesis; base; beta-Galactosidase; cell killing; cell type; clinically relevant; cytokine; effective therapy; killings; macrophage; monocyte; mortality; novel; novel therapeutics; oxidized lipid; oxidized low density lipoprotein; programs; public health relevance; senescence; tool

 DESCRIPTION (provided by applicant): Atherosclerosis is one of the most common age-related causes of morbidity and mortality. The underlying causes of the progression from clinically-silent, benign disease to rupture-prone vulnerable plaques are incompletely understood, but include plaque destabilizing protease and inflammatory factor production. One potential source of these factors is the secretome of senescent cells, which have been hypothesized to accumulate in plaques based on senescence-associated β-galactosidase staining of lesions. The role of senescent cells in atherogenesis remained unclear without the availability of transgenic tools to selectively remove these cells. To address this technical defict, in preliminary studies we demonstrated that drug- inducible killing of senescent cells using the 3MR transgene resulted in reduced plaque size and number. This observation, in addition to overlap between pro-atherogenic factors and components of the senescent secretome, led to the central hypothesis that senescent cells drive atherogenesis and plaque destabilization via their pro-inflammatory, proteolytic secretome. To test this hypothesis, we will pursue three aims. In the first aim, we will identify the stage of atherosclerosis at which senescence occurs and which cells become senescent. In the second aim, we will identify the mechanisms by which these cells become senescent and how they promote plaque formation. In the third aim, we will test whether senescent cell killing promotes beneficial remodeling or regression of established plaques. The long-term goal of our research is to target senescent cells for killing as a novel therapy for age-related diseases, such as atherosclerosis. The overall impact of this project is that it will increase our knowledge of basic atherosclerosis biology and integrate cellular senescence into our models of this disease. Further, completion of this research may justify targeting senescent cells as a therapeutic intervention in cardiovascular disease.

 描述（由适用提供）：动脉粥样硬化是发病和死亡率最常见的原因之一。从临床上有利，良性疾病到易受破坏的脆弱斑块的进展的根本原因尚不完全理解，但包括斑块不稳定蛋白酶和炎症因子的产生。这些因素的一个潜在来源是感觉细胞的分泌组，这些细胞已被认为是基于衰老相关的β-半乳糖苷酶染色在斑块中积累的。敏感细胞在动脉粥样硬化中的作用尚不清楚，没有转基因工具可有选择地去除这些细胞。为了解决这一技术定义，在初步研究中，我们证明了使用3MR转化的药物诱导的杀死感应细胞导致牙菌斑的大小和数量减少。除了促动脉粥样硬化因素和Sentence Servineme的组成部分之间的重叠外，这一观察结果还导致了一个中心假设，即感觉细胞通过其促炎性蛋白水解分泌组促进了动脉粥样硬化和斑块不稳定。为了检验这一假设，我们将追求三个目标。在第一个目标中，我们将确定发生感应的动脉粥样硬化阶段，以及哪些细胞变得有感觉。在第二个目标中，我们将确定这些细胞变得感觉的机制以及它们如何促进牙菌斑的形成。在第三个目标中，我们将测试感官杀伤是否促进已建立斑块的有益的重塑或回归。我们研究的长期目标是靶向感官细胞，以杀死作为年龄相关疾病（例如动脉粥样硬化）的新疗法。该项目的总体影响是，它将增加我们对基本动脉粥样硬化生物学的了解，并将细胞感知整合到我们的疾病模型中。此外，这项研究的完成可能证明靶向感觉细胞是对心血管疾病的治疗干预措施的合理性。