Cardiac hypertrophy and SERCa2 gene expression

心脏肥大和 SERCa2 基因表达

• 批准号: 7000355
• 负责人: Wolfgang H Dillmann
• 金额: $ 33.88万
• 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 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7000355
• 关键词: calcium binding protein; calcium channel; calcium flux; calcium transporting ATPase; cardiac myocytes; gene expression; genetically modified animals; heart failure; laboratory mouse; laboratory rat; mitochondria; protein localization; sarcoplasmic reticulum; transfection; ventricular hypertrophy

DESCRIPTION (provided by applicant): Heart failure (HF) is an important clinical problem and abnormalities in cardiac myocyte (CM) calcium (Ca) handling make a significant contribution to contractile dysfunction. Increasing the activity of the Ca ATPase of the Sarcoplasmic reticulum (SERCa2) in hearts with pressure overload (PO) induced cardiac hypertrophy (CH) and decreased contractile function improves the Ca transient and leads to enhanced contractile performance. The long-term positive or negative consequences of conditional increases in SERCa2 activity at different stages of cardiac hypertrophy and heart failure (HF) are however unclear. In aim I, we will determine the long term positive or negative consequences of increasing SERCa2 activity in a conditional, inducible fashion to enhance the delayed diastolic Ca transient in hearts with PO induced HF. Our preliminary results indicate that increasing SERCa2 activity in PO mice with overt HF, may further curtail a limited energetic supply and impair work output. We will explore if increasing SERCa2 activity in a conditional, timed manner in hearts with different degrees of CH and HF can still improve the Ca transient and contractile function. Adeno associated virus based transgene delivery and transgenic animals allowing for tetracycline system or Cre LoxP based "stuffer" removal with conditional increases in SERCa2 activity are used. Abnormal Ca handling and contractile function in CH/HF hearts may be in part mediated by decreased sarcoplasmic reticulum (SR) Ca loading due to an increased diastolic Ca leak. In aim II, we will explore mechanisms to diminish the SR Ca leak using potentially ryanodine receptor interacting proteins like Sorcin, FKB12.6, and Homer1c. Our preliminary show significant positive effects of FKBP12.6,Sorcin on SR Ca loading. In aim III, we will pursue our preliminary findings that mitochondrial (Mito) Ca flux is abnormal in CM obtained from failing hearts and determine the underlying mechanisms. We will also pursue our preliminary results that Sorcin localizes to mitochondria and markedly improves abnormal Mito Ca handling. In addition, we will determine if HF induces changes in Mito Ca handling is correlated with diminished high-energy phosphate production and can be reverted towards normal.

描述（由申请人提供）：心力衰竭（HF）是一个重要的临床问题，心肌细胞（CM）钙（Ca）处理异常对收缩功能障碍有重要影响。在压力超负荷 (PO) 诱导的心脏肥大 (CH) 和收缩功能下降的心脏中，增加肌浆网 Ca ATP 酶 (SERCa2) 的活性可改善 Ca 瞬态并导致收缩性能增强。然而，在心脏肥大和心力衰竭（HF）的不同阶段，SERCa2 活性有条件增加的长期积极或消极后果尚不清楚。在目标 I 中，我们将确定以有条件的诱导方式增加 SERCa2 活性的长期积极或消极后果，以增强 PO 诱导的心力衰竭心脏中延迟的舒张期 Ca 瞬变。我们的初步结果表明，增加明显心衰 PO 小鼠的 SERCa2 活性可能会进一步减少有限的能量供应并损害工作输出。我们将探讨在不同程度的 CH 和 HF 心脏中，有条件、定时地增加 SERCa2 活性是否仍能改善 Ca 瞬态和收缩功能。使用基于腺相关病毒的转基因递送和转基因动物，允许四环素系统或基于Cre LoxP的“填充物”去除，并有条件地增加SERCa2活性。 CH/HF 心脏中异常的 Ca 处理和收缩功能可能部分是由舒张期 Ca 渗漏增加导致的肌浆网 (SR) Ca 负荷减少介导的。在目标 II 中，我们将探索使用潜在的兰尼碱受体相互作用蛋白（如 Sorcin、FKB12.6 和 Homer1c）来减少 SR Ca 渗漏的机制。我们的初步结果显示 FKBP12.6、Sorcin 对 SR Ca 负载有显着的积极影响。在目标 III 中，我们将追求我们的初步发现，即从衰竭心脏获得的 CM 中线粒体 (Mito) Ca 通量异常，并确定其潜在机制。我们还将追求我们的初步结果，即 Sorcin 定位于线粒体并显着改善异常的 Mito Ca 处理。此外，我们将确定 HF 引起 Mito Ca 处理的变化是否与高能磷酸盐生成减少相关，并且可以恢复正常。