Resolution of inflammation in healing myocardial infarcts.

治愈心肌梗塞过程中炎症的消退。

• 批准号: 10814032
• 负责人: Nikolaos G Frangogiannis
• 金额: $ 5.42万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-15 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10814032
• 关键词: Age; Aging; Animals; Biological Assay; Cardiac; Cardiovascular system; Development; Effector Cell; Elderly; Equilibrium; Extracellular Matrix; Fibroblasts; Fibrosis; Functional disorder; Goals; Harvest; Heart; Heart Diseases; High Prevalence; In Vitro; Inflammation; Investigation; Knockout Mice; Longevity; Mediating; Mus; Myocardial; Myocardial Infarction; Myofibroblast; Parents; Pathogenesis; Patients; Phenotype; Production; Proliferating; Regulation; Resolution; Signal Transduction; Small Interfering RNA; Testing; United States National Institutes of Health; Work; coronary fibrosis; experimental study; healing; in vivo; knock-down; migration; parent grant; senescence

ABSTRACT: The proposed supplement will extend the studies of the parent grant to investigate fibroblast- specific actions of Smad1, and Smad2/3 in aging hearts. Study across the lifespan is a major priority of the NIH, and is particularly important in cardiovascular investigations, due to the high prevalence of heart disease in the elderly. The parent proposal explores effects of Smad1 vs Smad2/Smad3 signaling in reparative fibrosis. This supplement will extend these experiments in older animals to test the hypothesis that age-associated perturbations of the balance between fibroblast Smad1 and Smad2/3 signaling may be implicated in the pathogenesis of age-associated fibrosis and diastolic dysfunction. The hypothesis will be tested in 2 specific aims: Aim 1 will study the in vivo effects of fibroblast-specific Smad1, Smad2 and Smad3 signaling in aging hearts. Fibroblast-specific KOs generated in the parent grant will be used to examine effects of the Smads on age-associated fibrosis, remodeling and dysfunction.. Aim 2 will investigate the in vitro effects of Smad1 and Smad2/3 knockdown on senescent cardiac fibroblast phenotype and function. siRNA KD and Cre-mediated Smad deletion approaches (used in the parent grant) will be performed in cardiac fibroblasts harvested from young and old mice. Functional assays examining fibroblast migration, proliferation and myofibroblast conversion will be performed.

抽象的： 拟议的补充剂将扩展父母赠款的研究，以研究成纤维细胞 - Smad1的特定动作和衰老心脏中的Smad2/3。整个生命周期的研究是主要的 NIH的优先级，在心血管调查中尤其重要 老年人心脏病的患病率。父母提案探讨了smad1 vs的影响 修复性纤维化中的Smad2/Smad3信号传导。这种补充将把这些实验扩展到 老年动物测试了与年龄相关的扰动的假设 成纤维细胞SMAD1和SMAD2/3信号传导可能与年龄相关的发病机理有关 纤维化和舒张功能障碍。该假设将以两个特定目的进行检验： AIM 1将研究成纤维细胞特异性SMAD1，SMAD2和SMAD3信号的体内效应 老化的心。父母赠款中生成的成纤维细胞特异性KO将用于检查效果 与年龄相关的纤维化，重塑和功能障碍的SMAD。 AIM 2将研究SMAD1和SMAD2/3敲低对衰老心脏的体外影响 成纤维细胞表型和功能。 siRNA KD和CRE介导的SMAD缺失方法（使用 在父母的赠款中）将以年轻和老鼠收获的心脏成纤维细胞进行。 功能分析检查成纤维细胞迁移，增生和成肌纤维细胞转换将会 被执行。