CARDIAC HYPERTROPHY AND FAILURE IN TRANSGENIC MOUSE

拟议研究的总体目标是研究钙调蛋白是如何 过度表达会导致心肌细胞肥大和增殖，并 也许是心力衰竭。钙调素(CaM)是细胞内普遍存在的一种钙离子 已知在多种细胞类型中调节细胞增殖的受体；我们 研究表明，钙调素水平的增加是通过 心钠素(ANF)启动子在转基因小鼠中的表达 以心肌细胞过度肥大为特征的心脏增大 增生症。此外，新生婴儿死亡率过高。 表达最高水平CaM的转基因小鼠品系。第一 目的是评估过早死亡的转基因小鼠与 具有正常寿命的转基因小鼠。方法是检查凸轮 与生长有关的基因(即原癌基因)的水平、表达或 肥厚的标志物和激活的多功能的相对水平 Ca2+/CaM蛋白激酶II(CaMK II)--一种潜在的介导物或CaM 效果。目标2是确定重新诱导或持续抖动的效果 CaM在转基因小鼠脑室的表达。两种方法 将用于：(1)在成年动物体内重新诱导CaM转基因 现有的品系使用已知的诱导ANF启动子的药理学试剂， 再次检查随着时间的推移，心脏大小、死亡率和 上述基因的表达；以及(2)开发一种新的 通过iso=-ANF靶向心脏表达CaM的转基因小鼠 启动子；使用该启动子应导致CaM的持续表达 在脑室进入成年期。这些动物将被检查为 如上所述。这些研究可能会进一步定义CaM的关系 心肌细胞水平对生长反应和发育程度的影响 心力衰竭和可能识别基因表达的变化， 伴随着从心肌肥厚到心力衰竭的进展 模特。最终目的是检验CaMK II是 CaM诱导的心肌细胞生长反应。方法是 建立具有结构性活性CaMK II基因的转基因小鼠 心肌细胞特异性启动子的控制和心脏的特性 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.