CARDIAC HYPERTROPHY AND FAILURE IN TRANSGENIC MOUSE

转基因小鼠心脏肥大和衰竭

• 批准号: 6110454
• 负责人: ANTHONY R MEANS
• 金额: $ 25.99万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-01 至 2000-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6110454
• 关键词: atrial natriuretic peptide; calmodulin; calmodulin dependent protein kinase; cell growth regulation; congestive heart failure; disease /disorder model; disease /disorder proneness /risk; gene expression; genetic promoter element; genetically modified animals; heart dimension /size; heart ventricle; laboratory mouse; longevity; pathologic process; receptor coupling; recombinant DNA; second messengers; tissue /cell culture; transfection; ventricular hypertrophy

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.

拟议研究的总体目标是研究如何钙调蛋白 过表达会导致心肌肌细胞肥大和增生，以及 也许是心力衰竭。 钙调蛋白（CAM）是无处不在的细胞内Ca2+ 已知可以调节多种细胞类型的细胞增殖的受体；我们 已经表明，提高了针对心肌细胞的CAM水平 转基因小鼠中的心房亚替亚激素（ANF）启动子导致 心脏肿大的特征是夸张的肌细胞肥大和 增生。 此外，新生儿的死亡率过多 表达最高凸轮水平的转基因小鼠线。 第一个 目的是评估过早死亡的转基因小鼠 具有正常寿命的转基因小鼠。 方法是检查凸轮 水平，与生长有关的基因的表达（即原始基因）或 肥大的标记和活化多功能的相对水平 CA2+ /CAM蛋白激酶II（CAMK II），潜在的介体或CAM 影响。 AIM 2是确定抖动延迟或持续的效果 CAM在转基因小鼠的心室中的表达。 两种方法 将使用：（1）在成年动物中诱导凸轮转基因 使用已知诱导ANF启动子的药理剂的现有生产线 再次检查随着时间的时间，心脏大小，死亡率和 上面列出的基因的表达； （2）开发一条新线 由ISO = -ANF靶向心脏的CAM表达的转基因小鼠 发起人；该启动子的使用应导致CAM的持续表达 在心室成年。 这些动物将被检查为 上面描述。 这些研究可能会进一步定义CAM的关系 心肌细胞的水平达到生长反应和发育程度 心力衰竭，并可能确定基因表达的变化， 伴随着从心脏肥大到心力衰竭的进展 模型。 最终目的是检验CAMK II是核心的假设 CAM诱导的心肌细胞生长反应。 方法是 发展具有组成性活性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脏 这些动物的生长反应。