FAK Signaling in cardiac growth and hypertrophy

心脏生长和肥大中的 FAK 信号传导

基本信息

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
项目类别：
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

项目摘要

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端分化的细胞，其分裂能力非常有限，因此，对心脏的损伤通常会导致肌肉质量永久损失，导致心室功能障碍和心脏衰竭。因此，更好地了解如何控制心肌细胞周期，这应该增强我们为几种迄今可延期可延展心脏疾病提供有效治疗的能力。几项研究表明，发育中心的心肌细胞生长态与细胞外基质和整联蛋白受体表达的调节转移以及这些基质在体外支持心肌细胞生长的能力相关。这些数据强调了整联蛋白信号传导在调节心脏形态发生和心脏疾病进展方面的重要性，但是在心脏生长的不同阶段，这些过程如何进行微调。从过去的融资周期内完成的研究可以清楚地看出，FAK在发育过程中介导心肌细胞增殖，压力超负荷后的心肌细胞肥大以及缺血性侮辱后的心肌细胞存活。我们还提出了一个有趣的发现，即通过表达其内源性抑制剂FRNK在产后心脏中动态调节FAK活性。我们的结果表明，FRNK在心脏中瞬时表达，峰值水平发生后5-7天（就在细胞周期戒断之前），而FRNK的心脏选择性始于E10.5，导致严重的心室非compactication缺陷和胚胎致死性和与心脏障碍型成型cormoigaired coroneary coroneary polex polex polex preceiair preceiair coronation propix propive corecation preceiair preceair preceiaired perex preceiair perex preceiair perex preceiair coronation preceiair coroneary preceair prexecation。重要的是，超活活的FAK变体（BMHC-Superfak）的心室心肌细胞特异性表达能够挽救此表型，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信号传导的动态调节对于控制心肌细胞周期在发育过程中的戒断和可能对心脏应激响应细胞周期的重新输入至关重要。我们已经产生了许多转基因的功能获得/功能丧失小鼠模型，这将使我们能够检验这一假设并确定对FAK/FRNK对心肌细胞增殖的影响很重要的下游信号。此外，由于FAK信号传导受调节心脏发育和功能的许多环境线索的影响，我们强烈认为拟议研究的结果将对我们对先天性心脏病以及进展心力衰竭的理解具有广泛的意义。我们将利用转基因的小鼠，已建立的心脏细胞培养模型以及人类心脏存储库中的样本来识别调节先天性和心脏病的发病机理的FAK依赖机制。公共卫生相关性：我们努力理解调节心脏细胞分裂能力的分子机制，因为在几种先天性心脏病和心力衰竭的背景下，操纵此功能的策略可能是有效的。尽管心脏细胞在发育过程中可以进行分裂，但分裂的时间或位置的改变会导致先天性心脏病。此外，这些细胞失去了出生后不久分裂的能力，因此对心脏的任何损害都可能导致不可逆转的功能丧失。