FAK Signaling in cardiac growth and hypertrophy

心脏生长和肥大中的 FAK 信号传导

• 批准号: 7785173
• 负责人: Joan M Taylor
• 金额: $ 33.17万
• 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 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7785173
• 关键词: Acute; Adult; Asses; Birth; Buffers; Cardiac; Cardiac Myocytes; Cell Culture Techniques; Cell Cycle; Cell Cycle Regulation; Cells; Cephalic; Chronic; Clinical; Coronary; Coronary Arteriosclerosis; Cues; Cultured Cells; Cytokinesis; Data; Databases; Defect; Depressed mood; Development; Diagnosis; Disease; Down-Regulation; Embryo; FGF9 gene; Face; Failure; Fibroblast Growth Factor; Functional disorder; Funding; Genetic; Growth; Heart; Heart Diseases; Heart failure; Human; Hypertrophic Cardiomyopathy; Hypertrophy; Hypoxia; In Vitro; Injury; Integrins; Ischemia; Lead; Locales; Measures; Mechanical Stress; Mediating; Modeling; Molecular; Morphogenesis; Mus; Muscle Cells; Mutation; Myocardial; Myocardial Ischemia; Myocardium; Neonatal; PTK2 gene; PTPN11 gene; Pathogenesis; Patients; Phase; Phenocopy; Phenotype; Play; Population; Process; Protein Tyrosine Phosphatase; Recovery; Regulation; Reperfusion Therapy; Research; Role; Sampling; Signal Transduction; Staging; Stress; Syndrome; Testing; Time; Up-Regulation; Variant; Ventricular; Ventricular Dysfunction; Withdrawal; Work; base; clinically significant; congenital heart disorder; effective therapy; gain of function; heart cell; in vivo; inhibitor/antagonist; interest; loss of function; mouse model; muscle form; neovascularization; pressure; public health relevance; receptor; repository; response; selective expression

DESCRIPTION (provided by applicant): Adult mammalian cardiomyocytes are terminally differentiated cells with very limited capabilities to divide, thus, injury to the heart typically causes permanent loss of muscle mass leading to ventricular dysfunction and heart failure. Therefore, a better understanding of how the myocyte cell cycle is controlled should enhance our ability to provide effective therapy for several heretofore-intractable cardiac diseases. Several studies indicate that the cardiomyocyte growth state in the developing heart correlates with regulated shifts in the expression of extracellular matrix and integrin receptors and the ability of these matrices to support myocyte growth in vitro. These data underscore the importance of integrin signaling in regulating both cardiac morphogenesis and the progression of cardiac disease, but how these processes are fine-tuned during the different phases of cardiac growth is unknown. It is clear from our studies completed within the past funding cycle that FAK functions to mediate cardiomyocyte proliferation during development, cardiomyocyte hypertrophy following pressure overload, and cardiomyocyte survival following an ischemic insult. We have also made the interesting discovery that FAK activity is dynamically regulated in the post-natal heart by expression of its endogenous inhibitor, FRNK. Our results demonstrate that FRNK is transiently expressed in the heart with peak levels occurring 5-7 days post-natal (just prior to cell cycle withdrawal) and that cardiac-selective expression of FRNK starting at E10.5 leads to a severe ventricular non-compaction defect and embryonic lethality associated with impaired cardiomyocyte proliferation and impaired coronary plexus formation. Importantly, ventricular cardiomyocyte-specific expression of a super-activatable FAK variant (bMHC-SuperFAK) was able to rescue this phenotype, indicating a cell autonomous role for FAK in regulating these critical functions. Thus, our working hypothesis is that dynamic regulation of FAK signaling is important for the control of cardiomyocyte cell cycle withdrawal during development and perhaps to cell-cycle re-entry in response to cardiac stress. We have generated many genetically modified gain-of-function/loss-of-function mouse models that will allow us to test this hypothesis and to identify the downstream signals that are important for the effects of FAK/FRNK on cardiomyocyte proliferation. In addition, since FAK signaling is regulated by, or required for, the effects of many of the environmental cues that regulate cardiac development and function, we strongly feel that the results from the proposed studies will have broad implications on our understanding of congenital cardiac disease and on the progression heart failure. We will utilize genetically modified mice, established cardiac cell culture models, and samples from a human heart repository to identify FAK-dependent mechanisms that regulate the pathogenesis of congenital and acquired heart disease. PUBLIC HEALTH RELEVANCE: We strive to understand the molecular mechanisms that regulate the ability of heart cells to divide, since strategies to manipulate this function could be efficacious in the context of several congenital heart diseases and heart failure. While heart cells can undergo division during development, alterations of the timing or locale of division can lead to congenital heart disease. Furthermore, these cells lose the ability to divide shortly after birth, thus any damage to the heart can cause irreversible loss of function.

描述（由申请人提供）：成年哺乳动物心肌细胞是终末分化细胞，其分裂能力非常有限，因此，心脏损伤通常会导致永久性肌肉质量损失，导致心室功能障碍和心力衰竭。因此，更好地了解肌细胞周期是如何被控制的，将提高我们为一些迄今为止难治性心脏病提供有效治疗的能力。几项研究表明，心脏发育过程中心肌细胞的生长状态与细胞外基质和整合素受体表达的调控变化以及这些基质在体外支持心肌细胞生长的能力有关。这些数据强调了整合素信号在调节心脏形态发生和心脏病进展中的重要性，但这些过程如何在心脏生长的不同阶段进行微调尚不清楚。从我们在过去资助周期内完成的研究中可以清楚地看出，FAK在发育过程中介导心肌细胞增殖、压力过载后心肌细胞肥大以及缺血损伤后心肌细胞存活。我们还发现了一个有趣的发现，即FAK活性在出生后的心脏中是通过其内源性抑制剂FRNK的表达动态调节的。我们的研究结果表明，FRNK在心脏中短暂表达，峰值水平出现在出生后5-7天（就在细胞周期退出之前），FRNK在E10.5开始的心脏选择性表达导致严重的心室非压实缺陷和胚胎致死，与心肌细胞增殖受损和冠状动脉丛形成受损有关。重要的是，心室心肌细胞特异性表达一种超激活FAK变体（bMHC-SuperFAK）能够挽救这种表型，表明FAK在调节这些关键功能方面具有细胞自主作用。因此，我们的工作假设是，FAK信号的动态调节对于控制心肌细胞发育过程中的细胞周期退出以及可能对心脏应激反应中的细胞周期重新进入很重要。我们已经建立了许多基因改良的功能获得/功能丧失小鼠模型，这将使我们能够测试这一假设，并确定下游信号，这些信号对FAK/FRNK对心肌细胞增殖的影响很重要。此外，由于FAK信号受许多调节心脏发育和功能的环境因素的影响所调节或需要，我们强烈认为，拟议研究的结果将对我们对先天性心脏病和心力衰竭进展的理解具有广泛的意义。我们将利用转基因小鼠、已建立的心脏细胞培养模型和来自人类心脏库的样本来确定调节先天性和获得性心脏病发病机制的fak依赖性机制。