MOLECULAR MECHANISMS OF CARDIAC ONTOGENY AND HYPERTROPHY

在本申请中提出的研究的主要目标仍然是 阐明了与细菌产生有关的基本分子机制 心肌的正常表型和异常表型 发展和对不同生理和病理的反应 刺激物。为此，将追求三个主要的具体目标：一) 用一种新的方法鉴定和鉴定心脏谱系决定基因 新开发的分子方法和细胞系的结合 具有许多心肌细胞的特征。一旦被隔离， 涉及的基因(S)将被用来解剖从一个 未分化的中胚层细胞转化为心肌细胞。二)识别和 描述与终末分化有关的基因(S) 心肌细胞的表型及其明显的不可逆性退出 细胞周期。我们将利用各种已经失去的细胞系 致力于终极分化状态的能力以及 某些癌基因逆转终末分化的能力 州政府。三)鉴定和鉴定肌肉特异性转录 参与心脏α-和β-受体表达的因子(S) β-MHC基因。这两个基因包含一种肌肉特异性增强子，即 不受MyoD基因家族的调控。β-MGC基因的增强子 也受到甲状腺激素受体的负调节。这些 增强剂提供了识别心脏特异性的独特机会 参与表型产生的转录因子 在发育过程中的变化和对病理刺激的反应。 提出的实验解决了一些最基本的问题 心脏生物学，即心肌细胞的起源和 以及分化表型的产生和维持。 这些问题的答案在 心肌收缩能力的调节及其潜在的影响 心肌再生。

The main goal of the research proposed in this application continues to be the elucidation of basic molecular mechanisms involved in the production of the normal and abnormal phenotype of the cardiac muscle, both during development and in response to diverse physiological and pathological stimuli. To this end, three main specific aims will be pursued: I) To identify and characterize cardiac lineage-determining genes using a combination of newly developed molecular approaches and cell lines that have many of the characteristics of cardiac cells. Once isolated, the gene(s) involved will be used to dissect the pathway leading from an undifferentiated mesodermal cell to a cardiocyte. II) To identify and characterize the gene(s) responsible for the terminally differentiated phenotype of cardiac cells and their apparent irreversible withdrawal from the cell cycle. We will make use of a variety of cell lines that have lost the ability to commit to the terminally differentiated state as well as the ability of certain oncogenes to reverse the terminally differentiated state. III) To identify and characterize muscle specific transcription factor(s) that are involved in the expression of the cardiac alpha- and beta-MHC genes. These two genes contain a muscle specific enhancer that is not regulated by the MyoD gene family. The enhancer on the beta-MGC gene is also negatively regulated by the thyroid hormone receptor. These enhancers provide a unique opportunity to identify cardiac-specific transcriptional factors that are involved in the production of phenotypic changes during development and in response to pathologic stimuli. The experiments proposed address some of the most fundamental questions of cardiac biology, namely, the origin of the cardiac myocyte and the production, as well as the maintenance, of the differentiated phenotype. The answer to these questions has significant practical import in the modulation of cardiac contractility and the potential to affect regeneration of the myocardium.