FAK signaling in cardiac growth and hypertrophy

心脏生长和肥大中的 FAK 信号传导

• 批准号: 6956467
• 负责人: Joan M Taylor
• 金额: $ 32.68万
• 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 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6956467
• 关键词: biological signal transduction; cardiac myocytes; cardiogenesis; enzyme activity; focal adhesion kinase; gene expression; genetically modified animals; guanosinetriphosphatases; heart dimension /size; heart enlargement; immunocytochemistry; laboratory mouse; mass spectrometry; microarray technology; mitogen activated protein kinase; pathologic process; phosphotransferases; tissue /cell culture; ventricular hypertrophy

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，整联蛋白结合粘附受体（5E1等）可以调节心脏的形式和功能。整联蛋白结扎促进了将许多结构和信号分子募集到腹侧质膜上，共同称为“局灶性粘附”，可将细胞内部产生力的肌动蛋白细胞骨架与细胞外矩阵（ECM）联系起来，并与下游信号通道的激活相结合。非受体酪氨酸激酶，局灶性粘附激酶（FAK）都被整合素和生长因子强烈激活，并且可能是在生长和发育过程中从这些不同途径中整合下游信号的候选者。实际上，FAK的种系缺失会导致中胚层缺损和E7.5-10之间的胚胎致死性，类似于在纤连蛋白 - 和D5-NULL小鼠中观察到的表型。尽管FAK在心脏发育中的直接作用尚未受到研究，但FAK-NULL胚胎的心脏显示出缺乏单独的中心脏和心内膜层，这表明心肌细胞的成熟缺陷。有趣的是，我们小组和其他人的最新工作清楚地表明，通过多种肥大刺激在培养的心肌细胞中激活FAK，包括苯肾上腺素（PE），内皮素I（ET-1），血管紧张素II（AII）（AII）和低渗透性压力，以及心脏fak fak Active的性能增加了心脏fak活性，这会增加心脏的心脏。从我们的精确发现中可以明显看出，FAK激活在心肌细胞肥大的发展中起着直接作用的想法，即FAK的激活对于PE刺激的培养细胞的PE刺激性肥大所必需，而其他人的类似发现则表明，FAK对于最大ET-1所需的FAK是最大的ET-1和伸展性诱导的体外肥大。该提案的实验目标是检验以下假设，即FAK调节体内心脏发育和病理肥大，并确定这些过程中涉及的FAK依赖性信号通路。我们将生成转基因的小鼠，其中使用CRE/LOXP技术以时间和心脏限制的方式删除FAK，以检查FAK在心脏增长中的功能作用。我们还将建立一个心脏细胞培养模型，以鉴定由肥大刺激差异调节的FAK依赖性信号和靶基因。