Calcium Cycling Protein Mutations in Human Heart Failure

人类心力衰竭中的钙循环蛋白突变

基本信息

  • 批准号:
    7312576
  • 负责人:
  • 金额:
    $ 48.55万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2006
  • 资助国家:
    美国
  • 起止时间:
    2006-01-01 至 2009-12-31
  • 项目状态:
    已结题

项目摘要

The depressed calcium cycling in animal models of heart failure and human failing hearts has been suggested to reflect, at least in part, the impaired calcium sequestration by the sarcoplasmic reticulum (SR). Calcium sequestration by the SR is mediated by a Ca2+-transport ATPase (SERCA2), whose activity is reversibly regulated by the phosphorylation status of phospholamban (PLN). Dephosphorylated PLN is an inhibitor of the Ca-affinity of SERCA2 and cardiac contractility, while phosphorylation of PLN relieves the inhibitory effects. The levels of PLN have been shown to be a major determinant of basal contractility and the heart's responses to 13-agonists. In human heart failure, the levels of PLN relative to SERCA2 are increased, resulting in increased inhibition of the Ca-pump's Ca-affinity and prolonged relaxation. In addition, the phosphorylation status of PLN is decreased, resulting in increased inhibitory function by PLN and further depression of SR Ca-cycling. The decreased PLN phosphorylation reflects increases in the PLN phosphatase 1 activity, partially due to dephosphorylation and attenuation of the inhibitor 1 (I-1) function. Thus, these two major Ca-regulatory proteins become our focus of attention in heart failure and it is important to determine whether genetic variations, such as point mutations, may occur in the PLN and I-1 human genes, which may alter their activities and modify the clinical course of the disease. Indeed, we have recently identified two human PLN mutations that led to dilated cardiomyopathy and heart failure at a young age. We propose here to continue our studies on identification of additional mutations in the PLN as well as the 1-1 genes and determine their functional significance and pathophysiological relevance, utilizing expression systems and genetically altered mice. In parallel, the subjects with the identified mutation will be closely followed to assess their cardiac function, exercise tolerance and force-interval relations (mechanical and relaxation restitution). Our findings will determine whether correlations may be established between a specific mutation in PLN or 1-1 and a specific clinical parameter or the time course of heart failure. Furthermore, these studies will provide valuable insights into the mechanisms by which specific genetic variants alter SR Ca-handling and function in heart failure.
心力衰竭动物模型和人类心脏衰竭的钙循环抑制被认为至少部分反映了肌浆网(SR)钙隔离受损。 SR 的钙封存是由 Ca2+ 转运 ATP 酶 (SERCA2) 介导的,其活性受到受磷蛋白 (PLN) 磷酸化状态的可逆调节。去磷酸化的 PLN 是 SERCA2 的 Ca 亲和力和心肌收缩力的抑制剂,而 PLN 的磷酸化可缓解抑制作用。 PLN 水平已被证明是基础收缩力和心脏对 13 激动剂反应的主要决定因素。在人类心力衰竭中,PLN 相对于 SERCA2 的水平增加,导致对 Ca 泵的 Ca 亲和力的抑制增加并延长松弛时间。此外,PLN 的磷酸化状态降低,导致 PLN 的抑制功能增强,并进一步抑制 SR Ca 循环。 PLN 磷酸化的降低反映了 PLN 磷酸酶 1 活性的增加,部分原因是去磷酸化和抑制剂 1 (I-1) 功能的减弱。因此,这两种主要的 Ca 调节蛋白成为我们在心力衰竭中关注的焦点,确定 PLN 和 I-1 人类基因中是否可能发生遗传变异(例如点突变)非常重要,这可能会改变它们的活性并改变疾病的临床病程。事实上,我们最近发现了两种导致年轻时扩张型心肌病和心力衰竭的人类 PLN 突变。我们在此建议继续研究鉴定 PLN 以及 1-1 基因中的其他突变,并确定它们的功能意义和病理生理学相关性, 利用表达系统和基因改造小鼠。与此同时,将密切跟踪具有已识别突变的受试者,以评估他们的心脏功能、运动耐量和力量-间隔关系(机械和松弛恢复)。我们的研究结果将确定 PLN 或 1-1 的特定突变与特定临床参数或心力衰竭时程之间是否可以建立相关性。此外,这些研究将为特定基因变异改变 SR Ca 处理和心力衰竭功能的机制提供有价值的见解。

项目成果

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Evangelia G Kranias其他文献

Unleashing the Power of Genetics: PLN Ablation, Phospholambanopathies and Evolving Challenges.
释放遗传学的力量:PLN 消融、磷酸化病和不断变化的挑战。
  • DOI:
  • 发表时间:
    2024
  • 期刊:
  • 影响因子:
    20.1
  • 作者:
    Alicia Mattiazzi;Evangelia G Kranias
  • 通讯作者:
    Evangelia G Kranias
Physiologic and Molecular Changes Reflecting Impaired Calcium Cycling in Pacing Induced Heart Failure in Immature Goats ♦ 83
反映未成熟山羊起搏诱发心力衰竭中钙循环受损的生理和分子变化♦83
  • DOI:
    10.1203/00006450-199804001-00104
  • 发表时间:
    1998-04-01
  • 期刊:
  • 影响因子:
    3.100
  • 作者:
    Anirban Banerjee;Sonali Shah;Preeti Joshi;Marjorie Gabel;Brain D Hoit;Evangelia G Kranias
  • 通讯作者:
    Evangelia G Kranias
Delayed Restitution of Contractility Reflects Impaired Calcium Handling in Pacing Induced Heart Failure in Immature Goats
收缩功能延迟恢复反映了未成熟山羊起搏诱导心力衰竭中钙处理受损
  • DOI:
    10.1203/00006450-199904020-00119
  • 发表时间:
    1999-04-01
  • 期刊:
  • 影响因子:
    3.100
  • 作者:
    Anirban Banerjee;Preeti Joshi;Judy M Harrer;Evangelia G Kranias;Brian D Hoit
  • 通讯作者:
    Brian D Hoit
Altered Atrial Function and Associated Changes in Proteins Responsible for Myocardial Contraction and Relaxation in Right Atria of Children With Tetralogy of Fallot • 84
法洛四联症患儿右心房心房功能改变及与心肌收缩和舒张相关蛋白的变化 • 84
  • DOI:
    10.1203/00006450-199804001-00105
  • 发表时间:
    1998-04-01
  • 期刊:
  • 影响因子:
    3.100
  • 作者:
    Anirban Banerjee;Dimple P Shah;Vivek J Kadambi;Peter B Manning;Evangelia G Kranias
  • 通讯作者:
    Evangelia G Kranias

Evangelia G Kranias的其他文献

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{{ truncateString('Evangelia G Kranias', 18)}}的其他基金

Understanding Cardiovascular Disease Mechanisms
了解心血管疾病机制
  • 批准号:
    10421306
  • 财政年份:
    2014
  • 资助金额:
    $ 48.55万
  • 项目类别:
Understanding Cardiovascular Disease Mechanisms
了解心血管疾病机制
  • 批准号:
    10176556
  • 财政年份:
    2014
  • 资助金额:
    $ 48.55万
  • 项目类别:
Understanding Cardiovascular Disease Mechanisms
了解心血管疾病机制
  • 批准号:
    8969700
  • 财政年份:
    2014
  • 资助金额:
    $ 48.55万
  • 项目类别:
Understanding Cardiovascular Disease Mechanisms
了解心血管疾病机制
  • 批准号:
    10009722
  • 财政年份:
    2014
  • 资助金额:
    $ 48.55万
  • 项目类别:
Understanding Cardiovascular Disease Mechanisms
了解心血管疾病机制
  • 批准号:
    8793244
  • 财政年份:
    2014
  • 资助金额:
    $ 48.55万
  • 项目类别:
Understanding Cardiovascular Disease Mechanisms
了解心血管疾病机制
  • 批准号:
    10640285
  • 财政年份:
    2014
  • 资助金额:
    $ 48.55万
  • 项目类别:
Calcium Cycling Protein Mutations in Human Heart Failure
人类心力衰竭中的钙循环蛋白突变
  • 批准号:
    7338017
  • 财政年份:
    2007
  • 资助金额:
    $ 48.55万
  • 项目类别:
Calcium Cycling Protein Mutations in Human Heart Failure
人类心力衰竭中的钙循环蛋白突变
  • 批准号:
    6892776
  • 财政年份:
    2005
  • 资助金额:
    $ 48.55万
  • 项目类别:
Genetic and Molecular Signaling in Heart Failure
心力衰竭的遗传和分子信号传导
  • 批准号:
    7564000
  • 财政年份:
    2005
  • 资助金额:
    $ 48.55万
  • 项目类别:
Genetic and Molecular Signaling in Heart Failure
心力衰竭的遗传和分子信号传导
  • 批准号:
    7338024
  • 财政年份:
    2005
  • 资助金额:
    $ 48.55万
  • 项目类别:

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醛固酮相关高血压与钙代谢之间的内分泌串扰
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