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(申请人提供)：动脉粥样硬化是最常见的与年龄有关的发病率和死亡率的原因之一。从临床上无症状的良性疾病发展到容易破裂的脆弱斑块的潜在原因尚不完全清楚，但包括斑块不稳定的蛋白酶和炎症因子的产生。这些因素的一个潜在来源是衰老细胞的分泌体，根据病变的衰老相关β-半乳糖苷酶染色，假设这些分泌体积聚在斑块中。衰老细胞在动脉粥样硬化形成中的作用尚不清楚，除非有选择性地移除这些细胞的转基因工具可用。为了解决这一技术缺陷，在初步研究中，我们证明了使用3MR转基因药物诱导的对衰老细胞的杀伤导致斑块大小和数量减少。除了促动脉粥样硬化因子和衰老分泌体成分之间的重叠外，这一观察还导致了中心假说，即衰老细胞通过其促炎症、蛋白分解的分泌体驱动动脉粥样硬化和斑块的不稳定。为了验证这一假设，我们将追求三个目标。在第一个目标中，我们将确定动脉粥样硬化发生衰老的阶段以及哪些细胞变得衰老。在第二个目标中，我们将确定这些细胞衰老的机制以及它们如何促进斑块形成。在第三个目标中，我们将测试衰老细胞杀伤是否促进已建立的斑块有益的重塑或消退。我们研究的长期目标是针对衰老细胞进行杀伤，作为一种治疗年龄相关疾病的新方法，如动脉粥样硬化。这个项目的总体影响是，它将增加我们对动脉粥样硬化生物学的基础知识，并将细胞衰老纳入我们的这种疾病模型。此外，这项研究的完成可能证明将衰老细胞作为心血管疾病的治疗干预是合理的。