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.

摘要： 拟议的补充将扩大父母补助金的研究，以调查成纤维细胞- Smad 1和Smad 2/3在衰老心脏中的特定作用。对整个生命周期的研究 这是NIH的优先事项，在心血管研究中尤其重要，因为高 老年人心脏病的患病率。母公司的提案探讨了Smad 1与 Smad 2/Smad 3信号在修复性纤维化中的作用这一补充将扩大这些实验， 年龄较大的动物，以测试假设，年龄相关的扰动之间的平衡， 成纤维细胞Smad 1和Smad 2/3信号转导可能与年龄相关性糖尿病的发病机制有关。 纤维化和舒张功能障碍。将在2个特定目标中检验该假设： 目的1将研究成纤维细胞特异性Smad 1、Smad 2和Smad 3信号转导在成纤维细胞中的作用。 衰老的心脏母细胞赠款中产生的成纤维细胞特异性科斯将用于检查影响 与年龄相关的纤维化、重塑和功能障碍。 目的2探讨Smad 1和Smad 2/3基因敲低对衰老心肌细胞凋亡的影响。 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。