Modulation of ERK signaling in cardiac growth

在这项提议中要检验的假设是，改变发育中器官的细胞数量可能会对成年期器官的功能产生影响。我们将把注意力集中在发展中的心脏。 这种选择是基于在发育过程中心肌细胞数量受到病理生理调节的能力。该项目资助的一个主要假设是，子宫内压力可以改变成年期细胞生长的程序。对于心脏，这通常与心肌细胞增生的刺激和成人心脏功能的改变有关。这一假说的一个推论是细胞数量的改变可以影响心脏功能。这将使用心脏功能的转基因动物模型进行测试。初步研究将确定心脏中细胞生长的程序（具体目标1）。随后的目标将测试的假设，修改ERK功能将在心脏发育过程中的细胞生长，并在成人心血管功能的后果。在特定目标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最大的关键时期。在具体目标2中，我们将这些ERK信号转导修饰剂引入到整个动物模型中，使其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对动物一生中心脏功能发育过程的改变具有病理生理学后果。

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.