CARDIAC HYPERTROPHY AND FAILURE IN TRANSGENIC MOUSE

这项研究的总体目标是研究钙调素 过表达引起心肌细胞肥大和增生， 可能是心力衰竭 钙调素（CaM）是一种普遍存在于细胞内的钙离子 已知在许多细胞类型中调节细胞增殖的受体;我们 已经表明，增加的钙调素水平针对心肌细胞，由 心房利钠激素（ANF）启动子在转基因小鼠中的作用导致 以过度的肌细胞肥大为特征的心脏增大， 增生 此外，新生儿的死亡率过高， 转基因小鼠系表达最高水平的钙调素。 第一 目的是评估过早死亡的转基因小鼠， 寿命正常的转基因小鼠。 方法是检查钙调素 与生长相关的基因（即原癌基因）的水平、表达或 肥大的标志物，以及活化的多功能 Ca 2 + /CaM蛋白激酶II（CaMK II），一种潜在的CaM介导剂， 效果 目的2是确定抖动再诱导或持续的影响 转基因小鼠心室中CaM的表达。 两种方法 将用于：（1）在成年动物中重新引入CaM转基因， 使用已知诱导ANF启动子的药理学试剂的现有细胞系， 再次检查随着时间的推移，心脏大小，死亡率， 以上列出的基因的表达;和（2）开发一个新的品系， 通过iso=-ANF靶向心脏表达CaM的转基因小鼠 启动子;该启动子的使用应导致CaM的持续表达 进入成年期。 将对动物进行检查， 上面描述 这些研究可进一步明确钙调素与细胞凋亡的关系。 心肌细胞中的水平与生长反应和发育的程度有关 并可能识别基因表达的变化， 伴随着从心脏肥大到心力衰竭的进展， 模型 最终的目的是检验CaMK II是 钙调素诱导的心肌细胞生长反应。 采取方法是 开发携带组成型活性CaMK II基因的转基因小鼠， 控制心肌细胞特异性启动子并表征心肌细胞特异性启动子的表达。 这些动物的生长反应。

The overall goal of the proposed research is to investigate how calmodulin overexpression causes cardiac myocyte hypertrophy and hyperplasia and perhaps heart failure. Calmodulin (CaM) is a ubiquitous intracellular Ca2+ receptor known to regulate cell proliferation in a number of cell types; we have shown that increased CaM levels targeted to cardiac myocytes by the atrial natriuretic hormone (ANF) promoter in transgenic mice lead to cardiac enlargement characterized by exaggerated myocyte hypertrophy and hyperplasia. Furthermore, there is excess mortality in neonates from the line of transgenic mice expressing the highest levels of CaM. The first aim is to evaluate transgenic mice that die prematurely compared with transgenic mice with normal lifespans. The approach is to examine CaM levels, expression of genes related to growth (i.e. proto-oncogenes) or are markers of hypertrophy, and relative levels of activated multifunctional Ca2+ /CaM protein kinase II (CaMK II), a potential mediator or the CaM effect. Aim 2 is to determine the effect of dither reinduced or persistent expression of CaM in the ventricles of transgenic mice. Two approaches will be used: (1) to reinduce the CaM transgene in adult animals of the existing lines using pharmacologic agents known to induce the ANF promoter, again examining changes, over time, in heart size, mortality, and expression of the genes listed above; and (2) to develop a new line of transgenic mice with CaM expression targeted to the heart by the iso=-ANF promoter; use of this promoter should result in continued expression of CaM in the ventricles into adulthood. The animals will be examined as described above. These studies may further define the relationship of CaM levels in cardiac myocytes to the degree of growth response and development of heart failure and possibly identify change in expression of genes, that accompany the progression from cardiac hypertrophy to heart failure in this model. The final aim is to test the hypothesis that CaMK II is central to the cardiomyocyte growth response induced by CaM. The approach is to develop transgenic mice bearing a constitutively active CaMK II gene under control of a cardiomyocyte specific promoter and characterize the cardiac growth response of these animals.