Adenylyl Cyclase and Cardiac Interstitium

腺苷酸环化酶和心脏间质

• 批准号: 7217649
• 负责人: PAUL A INSEL
• 金额: $ 38.13万
• 依托单位: VETERANS MEDICAL RESEARCH FDN/SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7217649
• 关键词: adenylate cyclase; biological signal transduction; cardiovascular disorder; cell proliferation; cyclic AMP; disease /disorder model; fibroblasts; fibrosis; immunocytochemistry; isozymes; laboratory mouse; laboratory rat; phenotype; polymerase chain reaction; protein kinase A; protein localization; tissue /cell culture; transfection; western blottings

Cardiac fibrosis, a pathological consequence of cardiac injury, can be manifest either as localized scar or more diffuse interstitial fibrosis. The cells responsible for cardiac fibrosis are cardiac fibroblasts, which numerically are the most prevalent cells in the heart. Cardiac fibroblasts are regulated by hormones, many of which act via plasma membrane receptors, including ones that are linked to heterotrimeric G proteins and G-protein- regulated effectors. One such effector, adenylyl cyclase, catalyzes the formation of cyclic AMP from ATP and is the focus of this proposal. Cyclic AMP has anti-fibrotic actions that include inhibition of the transformation of "resting" cardiac fibroblasts to pro-fibrogenic myofibroblasts. This proposal will test several hypotheses related to the ability of increased cyclic AMP formation, produced by enhanced expression of adenylyl cyclase-6 (AC-6), to alter biochemical and functional activities of cardiac fibroblasts. Studies will be conducted using primary cultures of cardiac fibroblasts and, in addition, will involve the use of an animal model (angiotensin infusion in rats and mice) that produces cardiac fibrosis. The experiments focus on AC-6 with an emphasis on its compartmentation with proximal and distal signaling components as well as impact of increased AC-6 expression on the fibrotic response, as assessed by several phenotypic characteristics. The results should provide proof-of-principle data regarding the potential for therapeutic targeting of cardiac fibroblasts by gene transfer with AC-6 and potentially other AC isoforms. It is likely that targeting of AC-6 to cardiac myocytes via intracoronary delivery of recombinant viral vectors (Project 1) will increase AC-6 expression in fibroblasts. The general hypothesis of Project 2 is that increased expression of AC-6 in cardiac fibroblasts will alter the fibrotic response and favorably modify cardiac remodeling to improve cardiac function in the failing heart.

心脏纤维化是心脏损伤的病理后果，可以表现为局部疤痕或 更多弥漫性间质纤维化。负责心脏纤维化的细胞是心脏成纤维细胞， 在数值上是心脏中最普遍的细胞。心脏成纤维细胞受激素调节，许多 通过质膜受体起作用的，包括与异三体G蛋白和G蛋白相关的受体 受调节的效应子。一种这样的效应子，腺苷酸环化酶，催化从 ATP，是该提议的重点。环状AMP具有抗纤维化作用，包括抑制 将“静息”心脏成纤维细胞转化为促纤维肌纤维细胞。该建议将测试几个 与增加环状AMP形成的能力有关的假设，这是通过增强的表达而产生的 腺苷酸环化酶6（AC-6），以改变心脏成纤维细胞的生化和功能活性。研究将是 使用心脏成纤维细胞的一级培养物进行，此外，将涉及动物的使用 产生心脏纤维化的模型（大鼠和小鼠的血管紧张素输注）。实验侧重于AC-6 强调其与近端和远端信号成分的隔室以及影响 通过几种表型特征评估，在纤维化反应上的AC-6表达增加。 结果应提供有关心脏治疗靶向潜力的原则数据证明 通过AC-6和其他其他AC同工型通过基因转移的成纤维细胞。 AC-6的靶向可能 通过重组病毒载体的冠状动脉内递送（项目1）会增加AC-6的心肌细胞（项目1） 成纤维细胞中的表达。项目2的一般假设是心脏中AC-6的表达增加 成纤维细胞将改变纤维化反应，并有利地修饰心脏重塑以改善心脏 在失败的心脏中发挥作用。