Transcriptional regulatory complexes associated with cardiac hypertrophy

在成功解码人类基因组（即DNA序列）之后，一项主要任务是了解基因的活性如何随相应蛋白质的变化而变化。由于蛋白质是细胞结构和功能的重要组成部分，蛋白质的数量和质量的变化将对疾病的发生和进展起关键作用。众所周知，在心肌过度生长（即肥大）、衰老或跳动功能异常等情况下，心脏中的一组基因会发生改变（向上或向下）。这种基因活动改变的原因仍然知之甚少。尽管最近的遗传学或癌症研究已经揭示了DNA和DNA结合蛋白（称为组蛋白）在控制基因活性方面的重要作用，但很少在心脏中进行研究。在这个项目中，我们将验证我们的假设，即dna -组蛋白结构是控制衰老和患病心脏基因活动的关键因素。我们最近的研究结果支持了这一建议，研究表明，在肥大的心脏中，这种dna -组蛋白结构确实以一种与基因活性改变非常吻合的方式改变。我们计划了一系列的研究，以系统的方式检验这一假设。将使用一些复杂和尖端的技术和心脏肥厚的实验模型。我们将分析心脏中一些选定基因活动的变化，并分析特定区域dna组蛋白结构和化学修饰的变化。然后将这些变化联系在一起。我们还将探索调节dna -组蛋白结构的可能性，从而控制心脏肥厚的程度。该项目由在基因活动和心脏病研究方面具有丰富经验的科学家共同努力，极有可能产生新的信息并具有重大的治疗潜力。

Following the success in decoding human genome, i.e. DNA sequence, a major task is to understand how the activity of genes with consequent changes in respective proteins. As proteins are an important component for cell structure and function, such changes in quantity and quality of proteins will play a pivotal role to affect disease development and progression. It has been well known that a group of genes are altered (up or down) in the heart under conditions such as heart muscle overgrowth (ie hypertrophy), aging or of abnormal beating function. The reasons for such altered gene activity remain poorly understood. Although recent studies from research on genetics or cancer have revealed the important role of the DNA and DNA-bound proteins (called histone) in the control of gene activity, this has rarely been studied in the heart. In this project, we will test our hypothesis that DNA-histone structure is a key factor that control gene activities in ageing and diseased heart. This proposal is supported by our recent findings showing that in the hypertrophied heart, such DNA-histone structure did alter in such a way that fits well with alterations in gene activity. We have planned a series of studies to test this hypothesis in a systematic fashion. A number of sophisticated and cutting-edge techniques and experimental models of heart hypertrophy will be used. We will analyse changes in activities of a number of selected genes in the heart and also analyse changes in DNA-histone structures and chemical modifications at particular regions. These changes will then be linked together. We will also explore the possibility of modulating DNA-histone structure, thereby controlling the degree of cardiac hypertrophy. This project is the joint efforts of scientists with substantial experience in research on gene activity and heart diseases, and is highly likely to generate novel information to and hold significant therapeutic potential.