Analysis of vascular cell senescence to identify interventions in atherosclerosis

分析血管细胞衰老以确定动脉粥样硬化的干预措施

• 批准号: 10472344
• 负责人: Myriam Gorospe
• 金额: $ 22.22万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10472344
• 关键词: Aging; Angiogenic Factor; Animal Model; Atherosclerosis; Blood Vessels; CCL2 gene; Cell Adhesion Molecules; Cell Aging; Cells; Clinical; Development; Diabetes Mellitus; Dipeptidyl Peptidases; Disease; Disease Progression; Exhibits; Genes; Genomics; Heterogeneity; IL8 gene; Inflammation; Intercellular adhesion molecule 1; Interleukin-1; Interleukin-6; Intervention; Modeling; Pathology; Phenotype; Play; Production; Role; Surface; Techniques; Therapeutic; Therapeutic Intervention; Vascular Diseases; Vascular Endothelial Growth Factors; age related; chemokine; cytokine; glucose metabolism; healthspan; improved; in vivo; inhibitor/antagonist; innovation; interest; normal aging; novel; senescence; single-cell RNA sequencing; systemic inflammatory response

The development of age-related multi-factorial diseases such as atherosclerosis is associated with persistent systemic inflammation. However, the interplay between aging, inflammation, and VSMC senescence is not well understood. Senescent cells exhibit a senescence-associated secretory phenotype (SASP) that includes the production of many proinflammatory cytokines (e.g., IL-6, IL-8, and IL-1), as well as chemokines (e.g., CCL2), adhesion molecules (e.g., ICAM-1), and angiogenic factors (e.g., VEGF). Recently, we found that Dipeptidyl peptidase 4 (DPP4) is highly expressed on the surface of senescent cells. While the effect of DPP4 on VSMCs is not well understood, DPP4 inhibitors such as Vildagliptin are clinically used to treat Diabetes. In animal models, gliptins have shown the ability to reduce atherosclerosis and inflammation, independent of DPP4s canonical role in glucose metabolism. Thus, we proposed to investigate the ability of DPP4 inhibitors to reduce the burden of senescent VSMCs in vascular disease progression.

与年龄相关的多因素疾病如动脉粥样硬化的发展与持续的全身炎症有关。 然而，衰老，炎症和VSMC衰老之间的相互作用还没有得到很好的理解。 衰老细胞表现出衰老相关分泌表型（SASP），其包括许多促炎细胞因子（例如，IL-6、IL-8和IL-1），以及趋化因子（例如，CCL 2），粘附分子（例如，ICAM-1）和血管生成因子（例如，VEGF）。 最近，我们发现二肽基肽酶4（Dipeptidyl peptidase 4，DPP 4）在衰老细胞表面高度表达。 虽然DPP 4对VSMC的作用还不清楚，但DPP 4抑制剂如维达利在临床上用于治疗糖尿病。 在动物模型中，格列汀类药物显示出减少动脉粥样硬化和炎症的能力，而不依赖于DPP 4在葡萄糖代谢中的典型作用。 因此，我们提出研究DPP 4抑制剂降低血管疾病进展中衰老VSMC负担的能力。