FAK signaling in cardiac growth and hypertrophy

心脏生长和肥大中的 FAK 信号传导

• 批准号: 7436305
• 负责人: Joan M Taylor
• 金额: $ 30.99万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-15 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7436305
• 关键词: Actins; Angiotensin II; Binding; Cardiac; Cardiac Myocytes; Cell membrane; Cells; Class; Cultured Cells; Cytoskeleton; Defect; Development; Embryo; Endothelin; Endothelin-1; Extracellular Matrix; Fibronectins; Focal Adhesion Kinase 1; Focal Adhesions; Gene Targeting; Genetic; Goals; Growth; Growth Factor; Growth and Development function; Heart; Hypertrophy; In Vitro; Integrins; Knockout Mice; Ligation; Link; Modeling; Mus; Numbers; Other Finding; Pathway interactions; Phenotype; Phenylephrine; Play; Process; Receptor Protein-Tyrosine Kinases; Role; Seminal; Signal Pathway; Signal Transduction; Signaling Molecule; Stimulus; Stress; Stretching; Technology; Testing; Work; adhesion receptor; heart function; in vivo

DESCRIPTION (provided by applicant): Recent genetic evidence indicates that the integrin class of fibronectin-binding adhesion receptors (5E1 and others) can regulate both the form and function of the heart. Integrin ligation drives recruitment of a number of structural and signaling molecules to the ventral plasma membrane collectively termed a "focal adhesion" which serves to link the force-generating actin cytoskeleton inside the cell to the extracellular matrix (ECM), and to coordinate activation of downstream signaling pathways. The non-receptor tyrosine kinase, Focal Adhesion Kinase (FAK) is strongly activated by both integrins and growth factors, and is a likely candidate to integrate downstream signals from these diverse pathways during growth and development. Indeed, germline deletion of FAK results in mesodermal defects and embryonic lethality between E7.5-10 similar to the phenotype observed in both fibronectin-, and D5-null mice. Although a direct role for FAK in cardiac development has yet to be examined, hearts from FAK-null embryos revealed a lack of separate mesocardial and endocardial layers, indicative of a defect in cardiomyocyte maturation. Interestingly, recent work by our group and others clearly indicate that FAK is activated in cultured cardiomyocytes by a variety of hypertrophic stimuli including, phenylephrine (PE), endothelin I (ET-1), angiotensin II (AII), and hypo-osmotic stress, and that increased cardiac FAK activity is observed in vivo in hypertrophic hearts. The idea that FAK activation plays a direct role in the development of cardiomyocyte hypertrophy is evident from our seminal findings that the activation of FAK is required for PE-stimulated hypertrophy of cultured cells and similar findings from others that FAK is required for maximal ET-1 and stretch-induced hypertrophy in vitro. The experimental goals of this proposal are to test the hypothesis that FAK regulates cardiac development and pathological hypertrophy in vivo and to identify the FAK-dependent signaling pathways involved in these processes. We will generate genetically modified mice in which FAK will be deleted in a temporal and cardiac-restricted fashion using Cre/LoxP technology to examine a functional role for FAK in cardiac growth. We will also establish a cardiac cell culture model to identify FAK-dependent signals and target genes that are differentially regulated by hypertrophic stimuli.

描述（由申请人提供）：最近的遗传证据表明，纤连蛋白结合粘附受体（5E 1和其他）的整合素类可以调节心脏的形式和功能。整合素连接驱动许多结构和信号分子募集到腹侧质膜，统称为“粘着斑”，其用于将细胞内产生力的肌动蛋白细胞骨架连接到细胞外基质（ECM），并协调下游信号传导途径的激活。非受体酪氨酸激酶，粘着斑激酶（FAK）被整合素和生长因子强烈激活，并且是在生长和发育期间整合来自这些不同途径的下游信号的可能候选者。事实上，FAK的生殖系缺失导致E7.5-10之间的中胚层缺陷和胚胎致死，类似于在纤连蛋白和D5缺失小鼠中观察到的表型。虽然FAK在心脏发育中的直接作用还有待研究，但来自FAK缺失胚胎的心脏显示缺乏单独的中膜层和内膜层，表明心肌细胞成熟缺陷。有趣的是，我们小组和其他人最近的工作清楚地表明，FAK在培养的心肌细胞中被各种肥大刺激激活，包括苯肾上腺素（PE），内皮素I（ET-1），血管紧张素II（AII）和低渗应激，并且在肥大心脏中观察到心脏FAK活性增加。FAK激活在心肌细胞肥大的发展中起直接作用的想法从我们的开创性发现中显而易见，即FAK的激活是PE刺激的培养细胞肥大所必需的，以及其他人的类似发现，即FAK是体外最大ET-1和牵张诱导的肥大所必需的。本实验的目的是验证FAK在体内调节心脏发育和病理性肥大的假说，并确定参与这些过程的FAK依赖性信号通路。我们将产生转基因小鼠，其中FAK将被删除的时间和心脏限制的方式使用Cre/LoxP技术检查FAK在心脏生长中的功能作用。我们还将建立一个心脏细胞培养模型，以确定FAK依赖的信号和靶基因，差异调节肥大刺激。