Adenylyl Cyclase and Cardiac Interstitium

腺苷酸环化酶和心脏间质

• 批准号: 7482977
• 负责人: PAUL A INSEL
• 金额: $ 35.64万
• 依托单位: VETERANS MEDICAL RESEARCH FDN/SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7482977
• 关键词: Adenoviruses; Adenylate Cyclase; Agonist; Angiotensins; Animal Model; Biochemical; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Caveolins; Cell membrane; Cell physiology; Cells; Cessation of life; Characteristics; Cicatrix; Class; Condition; Congestive Heart Failure; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Diffuse; Disease; Distal; Enzymes; Fibroblasts; Fibrosis; Forskolin; G-Protein-Coupled Receptors; G-substrate; GTP-Binding Proteins; Gene Transfer; Generations; Growth; Heart; Heterotrimeric GTP-Binding Proteins; Hormones; Hypertension; Infusion procedures; Injury; Intracellular Second Messenger; Link; Localized; Mediating; Membrane Microdomains; Mus; Muscle Cells; Myofibroblast; Pattern; Phosphorylation; Protein Isoforms; Protein Overexpression; Rattus; Recombinants; Rest; Role; Second Messenger Systems; Signal Transduction; Testing; Therapeutic; Viral Vector; Work; adenylyl cyclase 6; beta-adrenergic receptor; caveolin 1; design; extracellular; fibrogenesis; improved; in vivo; interstitial; irinotecan; novel; receptor; repaired; research study; response; scaffold; therapeutic target

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结果，可以表现为局部疤痕或 间质纤维化更加弥漫。导致心脏纤维化的细胞是心脏成纤维细胞， 从数量上看，它们是心脏中最常见的细胞。心脏成纤维细胞受多种激素的调节 通过质膜受体发挥作用，包括与异三聚体 G 蛋白和 G 蛋白相关的受体 受调节的效应器。其中一种效应物，腺苷酸环化酶，催化环 AMP 的形成 ATP 是本提案的重点。 Cyclic AMP 具有抗纤维化作用，包括抑制 “静止”心脏成纤维细胞向促纤维化肌成纤维细胞的转化。该提案将测试多项 与增加环 AMP 形成能力相关的假设，该能力是通过增强表达而产生的 腺苷酸环化酶-6 (AC-6)，改变心脏成纤维细胞的生化和功能活动。研究将是 使用心脏成纤维细胞的原代培养物进行，此外，还将涉及使用动物 产生心脏纤维化的模型（大鼠和小鼠血管紧张素输注）。实验重点是AC-6 重点是其与近端和远端信号成分的划分以及影响 通过几个表型特征评估，AC-6 表达增加对纤维化反应的影响。 结果应提供有关心脏治疗靶向潜力的原理验证数据 通过 AC-6 和可能的其他 AC 亚型进行基因转移来形成成纤维细胞。 AC-6 的目标很可能是 通过冠状动脉内递送重组病毒载体（项目 1）的心肌细胞将增加 AC-6 在成纤维细胞中表达。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改变心脏重塑以改善心脏功能 在衰竭的心脏中发挥作用。