Modulation of ERK signaling in cardiac growth

在这个提议中要测试的假设是，改变一个发育中的器官的细胞数量会对该器官在成年后的功能产生影响。我们将把注意力集中在心脏的发育上。这种选择是基于心脏细胞数量在发育过程中受到病理生理调节的能力。本项目的一个主要假设是，宫内压力可以改变成人生活中控制细胞生长的程序。对于心脏，这通常与心肌细胞增生的刺激和成人心功能的改变有关。这个假设的一个推论是细胞数量的改变可以影响心脏功能。这将使用转基因动物心功能模型进行测试。初步研究将确定心脏细胞生长的程序（特异性目标1）。随后的目标将验证这一假设，即改变ERK功能将对心脏发育过程中的细胞生长和成人心血管功能产生影响。在Specific Aim 1中，我们将确定心脏器官发生过程中ERK活性和增殖信号通路达到最大的关键时期。在Specific Aim 2中，我们将把这些ERK信号修饰剂引入到整个动物模型中，使它们的表达仅限于心肌细胞。在具体目标3中，我们将确定这些修饰剂是否具有动物一生中改变的发育过程对心脏功能的病理生理后果。

The hypothesis to be tested in this proposal is that modifying the cell number of a developing organ can have consequences on the organ's function during adult life. We will focus our attention on the developing heart. This choice is based on the ability of cardiac cell number to be regulated pathophysiologically during development. A major hypothesis of this Program Project Grant is that intrauterine stresses can modify the program governing cell growth in adult life. For the heart, this is often associated with the stimulation of cardiomyocyte hyperplasia and an alteration in adult heart function. A corollary of this hypothesis is that alterations in cell number can affect cardiac function. This will be tested using genetically modified animal models of cardiac function. Initial studies will determine the program of cell growth in the heart (Specific Aim 1). Subsequent Aims will test the hypothesis that modifying ERK function will have consequences on cell growth during cardiac development, and on cardiovascular function in the adult. In Specific Aim 1 we will determine the critical period when ERK activity and proliferative signals pathways are maximal during organogenesis of the heart. In Specific Aim 2 we will introduce these modifiers of ERK signaling into whole animal models in such a way that their expression limited to the cardiomyocyte. In Specific Aim 3 we will determine whether these modifiers have pathophysiological consequences of the altered developmental processes on heart function during he lifetime of the animal.