Modulation of ERK signaling in cardiac growth

心脏生长中 ERK 信号的调节

基本信息

批准号：
6595219
负责人：
PHILIP J.S. STORK
金额：
$ 31.28万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-06-01 至 2007-05-31
项目状态：
已结题

项目摘要

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.

该提案中要检验的假设是，修改发育器官的细胞数量可能会对成人生活中的功能产生影响。我们将把注意力集中在发展中的心中。此选择基于心脏细胞数在发育过程中受到病理生理调节的能力。该计划项目赠款的一个主要假设是，宫内压力可以改变成人生活中细胞生长的程序。对于心脏，这通常与刺激心肌细胞增生和成人心脏功能改变有关。该假设的必然性是细胞数的改变会影响心脏功能。这将使用心脏功能的转基因动物模型对此进行测试。最初的研究将确定心脏中细胞生长的程序（特定目标1）。随后的目标将检验以下假设：修改ERK功能将对心脏发育过程中的细胞生长以及成人的心血管功能产生影响。在特定目标1中，我们将确定在心脏器官发生过程中ERK活性和增殖信号途径最大的关键时期。在特定的目标2中，我们将以这些ERK信号传导的方式引入整个动物模型，以使它们的表达限于心肌细胞。在特定目标3中，我们将确定这些修饰符是否对动物一生中心脏功能的变化过程的病理生理后果产生。