Iroquois Homeobox Transcription Factors in Heart Development and Physiology

描述（申请人提供）：转录因子是器官发生的几个方面的关键调节因子，在心脏中，几个重要的dna结合转录因子是心脏细胞命运和器官发生的强大调节因子。研究较少的是转录因子在生理功能模式中所起的作用，例如传导系统的功能特化。这些功能与心脏的发育调节密切相关，可能是影响心脏生理的几种人类先天性心脏病（如心肌病和心律失常）的根源。Irx家族的转录因子正在成为一类关键的调节因子，对心脏生理过程的转录调节至关重要。Irx1-Irx6家族的6个成员在哺乳动物心脏发育中以不同但重叠的模式表达。初步结果表明，Irx基因在心脏发育的非常特定的方面是重要的，并且Irx基因之间的遗传冗余掩盖了它们在心脏发育中的真正作用。我们假设易洛魁同源盒（Irx）转录因子家族是关键的模式和分化因子，赋予细胞类型特异性的特性，以专门的心脏谱系，从而参与建立晚期胎儿心脏发育和出生后生理的重要方面。为了验证我们的假设，我们将研究Irx因子在调节发育中的心脏细胞类型特化的关键方面的特定和重叠功能。我们提出三个具体目标：明确Irx3在建立小鼠心脏远端传导系统的同一性中的作用。2. 阐明Irx3和Irx5在心脏发育和出生后心脏功能的转录程序中所起的重叠作用。3. 了解Irx蛋白功能的分子专门化。每个目标的结果所产生的信息将是至关重要的，我们的心脏模式的理解和机制，后期模式事件影响出生后的生理。这些发现将适用于心脏传导系统、心脏生长和器官发生过程中细胞间通讯的研究。获得的结果也将与影响这些过程的人类疾病相关，包括梗死后的心律失常和心力衰竭时的心脏重塑。公共卫生相关性：转录因子是开启或关闭其他基因的蛋白质，在心脏中，几个重要的转录因子对心脏的正常形成至关重要。转录因子在确保心脏形成后正常功能方面所扮演的角色研究得较少。这些功能很可能是影响心功能的几种人类心脏疾病的根源，如心肌病和心律失常。我们将研究小鼠心脏中转录因子的Irx家族，因为我们相信它们是建立心脏生理学重要方面的关键。获得的结果将与影响这些过程的人类疾病相关，包括梗死后的心律失常和心力衰竭时的心脏重塑。

DESCRIPTION (provided by applicant): Transcription factors are key regulators of several aspects of organogenesis, and in the heart, several important DNA-binding transcription factors are powerful regulators of cardiac cell fate and organogenesis. Less well studied are the roles played by transcription factors in patterning of physiological functions, such as the functional specialization of the conduction system. These functions are intimately linked to the developmental regulation of the heart and are likely to be at the root of several human congenital heart diseases that affect cardiac physiology, such as cardiomyopathies and arrhythmias. The Irx family of transcription factors is emerging as a key class of regulators that are crucial for the transcriptional regulation of cardiac physiological processes. Six members of the family, Irx1-Irx6, are expressed in distinct but overlapping patterns in the developing mammalian heart. Preliminary results indicate that Irx genes are important in very specific aspects of cardiac development, and that genetic redundancy between Irx genes masks their true roles in the developing heart. We hypothesize that the Iroquois homeobox (Irx) family of transcription factors are key patterning and differentiation factors that confer cell type-specific properties to specialized cardiac lineages, and thereby are involved in establishing important aspects of late fetal heart development and postnatal physiology. To test our hypothesis, we will examine the specific and overlapping functions of Irx factors in regulating key aspects of cell type specialization in the developing heart. We propose three Specific Aims: 1. To define the role of Irx3 in establishing the identity of the developing distal conduction system of the mouse heart. 2. To elucidate the overlapping roles played by Irx3 and Irx5 in establishing transcriptional programs in cardiac development and in postnatal heart function. 3. To understand the molecular specialization of Irx protein function. The information generated by the results of each aim will be crucial to our understanding of heart patterning and the mechanism by which late patterning events affect postnatal physiology. These findings will be applicable to the study of the cardiac conduction system, cardiac growth, and intercellular communication during organogenesis. The results obtained will also be relevant to human diseases that affect these processes, including arrhythmias after infarct and cardiac remodeling in heart failure. PUBLIC HEALTH RELEVANCE: Transcription factors are proteins that turn other genes on or off, and in the heart, several important transcription factors are essential for the normal formation of the heart. Less well studied are the roles played by transcription factors in making sure the heart functions properly after it has formed. These functions are likely to be at the root of several human heart diseases that affect cardiac function, such as cardiomyopathies and arrhythmias. We will study the Irx family of transcription factors in the mouse heart, as we believe that they are key to establishing important aspects heart physiology. The results obtained will be relevant to human diseases that affect these processes, including arrhythmias after infarct and cardiac remodeling in heart failure.