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： 拟议的补充将扩大家长资助的研究范围，以调查成纤维细胞 Smad1 和 Smad2/3 在衰老心脏中的具体作用。贯穿一生的学习是一个重要的 NIH 的优先事项，并且在心血管研究中尤其重要，因为高 老年人心脏病的患病率。家长提案探讨了 Smad1 与 修复性纤维化中的 Smad2/Smad3 信号传导。本补充将扩展这些实验 年长的动物来检验以下假设：与年龄相关的平衡的扰动 成纤维细胞 Smad1 和 Smad2/3 信号传导可能与年龄相关的发病机制有关 纤维化和舒张功能障碍。该假设将在 2 个具体目标中进行检验： 目标 1 将研究成纤维细胞特异性 Smad1、Smad2 和 Smad3 信号传导在体内的影响 衰老的心。母基金中生成的成纤维细胞特异性 KO 将用于检查效果 Smads 对年龄相关纤维化、重塑和功能障碍的影响。 目标 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 在父母资助中）将在从年轻和年老小鼠身上收获的心脏成纤维细胞中进行。 检查成纤维细胞迁移、增殖和肌成纤维细胞转化的功能测定将 被执行。