CARDIAC HYPERTROPHY AND SERCA2 GENE EXPRESSION

心脏肥大和 SERCA2 基因表达

• 批准号: 2460076
• 负责人: Wolfgang H Dillmann
• 金额: $ 25.92万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-08-01 至 1998-12-11
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2460076
• 关键词: Adenoviridae; calcium transporting ATPase; calmodulin dependent protein kinase; enzyme activity; gene induction /repression; genetically modified animals; heart contraction; heart enlargement; intracardiac pressure; laboratory mouse; laboratory rabbit; laboratory rat; molecular cloning; transcription factor; transfection /expression vector

Cardiac pump failure presents a major health problem and the molecular mechanisms which contribute to decreased cardiac contractility are activately investigated butt are currently largely unknown. In animals with pressure overload (PO) induced cardiac hypertrophy and in human beings in a majority of studies, a marked decrease in cardiac sarcoplasmic reticulum Ca2+ ATPase (SERCA2) mRNA, protein levels and enzyme activity occur resulting in delayed calcium transients which may contribute to slowed diastolic relaxation. The functional contribution which the lowering of SERCA2 activity makes to heart failure has not been fully explored and it is currently unclear if increased SERCA2 levels in PO failing hearts would improve contractile function. The molecular mechanisms leading to the decrease in the expression of the endogenous SERCA2 gene in PO hearts have also only been incompletely explored. We hypothesize that increasing SERCA2 enzyme levels in myocytes from PO failing hearts will improve contractile function and that alteration in specific nuclear factors and changes in signaling through specific pathways will contribute to decreased SERCA2 gene expression. To test this hypothesis, we will pursue three aims. In the first aim, we will determine if increasing SERCA2 levels by expressing a SERCA2 transgene in the heart of transgenic delivery of a replication deficient human adenovirus 5 vectors expressing the SERCA2 transgene (Adv5 SERCA2) in PO hearts leads to a significant increase in SERCA2 levels and improvement in contractile behavior towards the normal range. We have constructed such an adenovirus vector which expresses significant amounts of SERCA2 levels. The virally expressed SERCA2 protein is functional as indicated by infection of cardiac myocytes and obtaining an accelerated calcium transient in myocytes infected with this virus. PO hearts of rabbits and rats will be infected with ADV5 SERCA2 and SERCA2 activity and contractile function will be evaluated. In the third aim, we will determine which specific nuclear transcription factors and cellular signaling systems influence SERCA2 gene transcription and evaluate the participation of a limited number of such factors and signaling systems. A determination if increasing SERCA2 levels in PO hypertrophied hearts will improve cardiac function toward the normal range, and additional knowledge related to the molecular mechanisms which contribute to decreased cardiac function in PO hearts will result from this research effort.

心脏泵衰竭是一个主要的健康问题， 导致心肌收缩力降低的机制是 积极研究的对接目前在很大程度上是未知的。动物中 与压力超负荷（PO）诱导的心脏肥大和人类 在大多数研究中， 肌浆网Ca2+ ATP酶（SERCA2）mRNA、蛋白水平和 酶活性的发生导致延迟的钙瞬变， 有助于减缓舒张期松弛。功能贡献 SERCA2活性的降低导致心力衰竭的机制尚未得到证实。 目前尚不清楚增加的SERCA2水平是否会导致 PO衰竭心脏可改善收缩功能。分子 机制导致内源性的表达减少， PO心脏中的SERCA2基因也仅被不完全探索。我们 假设从PO开始肌细胞中SERCA2酶水平增加 衰竭的心脏将改善收缩功能， 特异性核因子和通过特异性核因子 这将导致SERCA2基因表达降低。测试 这个假设，我们将追求三个目标。在第一个目标中，我们将 确定是否通过表达SERCA2转基因来增加SERCA2水平 在复制缺陷型人的转基因递送的核心中， 在PO中表达SERCA2转基因（Adv5 SERCA2）的腺病毒5载体 心脏导致SERCA2水平显著增加， 收缩行为向正常范围发展。我们已经构建 这种腺病毒载体表达显著量的SERCA2 程度.病毒表达的SERCA2蛋白具有所示的功能 通过感染心肌细胞， 在感染该病毒的肌细胞中短暂存在。PO家兔心脏， 大鼠将感染ADV5 SERCA2和SERCA2活性， 将评价收缩功能。第三个目标，我们将 确定哪些特定的核转录因子和细胞 信号系统影响SERCA2基因转录，并评估 有限数量的这些因素和信号系统的参与。 PO肥大心脏中增加SERCA2水平的确定 将改善心脏功能向正常范围，并额外 与分子机制相关的知识， 本研究将导致PO心脏的心功能下降 努力