Modulation of ERK signaling in cardiac growth

这项提议要检验的假设是，修改发育中器官的细胞数量可能会对成年后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上。这一选择是基于心脏细胞数量在发育过程中被病理生理调节的能力。该项目的一个主要假设是，宫内应激可以改变成人生活中控制细胞生长的程序。对于心脏来说，这通常与刺激心肌细胞增殖和成人心脏功能改变有关。这一假设的一个推论是，细胞数量的变化会影响心脏功能。这将使用转基因的心脏功能动物模型进行测试。初步研究将确定细胞在心脏中的生长计划(具体目标1)。随后的目标将检验这样一个假设，即修改ERK功能将对心脏发育过程中的细胞生长和成年人的心血管功能产生影响。在特定的目标1中，我们将确定ERK活性和增殖信号通路在心脏器官发生过程中达到最大值的关键时期。在特定的目标2中，我们将把这些ERK信号的修饰物引入整个动物模型，使它们的表达仅限于心肌细胞。在特定的目标3中，我们将确定这些修饰物是否在动物有生之年对心脏功能的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.