Regulation of Sarcoplasmic Reticulum Calcium Release in Heart Failure

心力衰竭肌浆网钙释放的调节

• 批准号: 9234581
• 负责人: Xander H.T. Wehrens
• 金额: $ 39.63万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2020-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9234581
• 关键词: Affect; Age-Years; Binding; Biochemical; Calcium; Cardiac; Cardiac Myocytes; Cause of Death; Cell membrane; Cells; Confocal Microscopy; Congestive Heart Failure; Cost of Illness; Coupling; Cyclic AMP-Dependent Protein Kinases; Data; Development; Disease; Down-Regulation; Echocardiography; Functional disorder; Gene Expression; Gene Proteins; Gene Transfer; Gene-Modified; Genes; Goals; Grant; Heart; Heart failure; Hospitalization; Image; Impairment; Knock-in Mouse; Knockout Mice; Lead; Link; Macromolecular Complexes; Mediating; Modeling; Molecular; Monitor; Mus; Muscle Cells; Pathogenesis; Patients; Peptides; Pharmacology; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphorylation Site; Phosphotransferases; Play; Post-Translational Protein Processing; Procedures; Protein Isoforms; Proteins; Proteomics; Regulation; Role; Ryanodine Receptor Calcium Release Channel; Ryanodine Receptors; Sarcoplasmic Reticulum; Site; Site-Directed Mutagenesis; Striated Muscles; Testing; Ventricular; Work; calmodulin-dependent protein kinase II; constriction; deletion analysis; experimental study; member; mutant; novel; novel therapeutics; obscurin; overexpression; public health relevance; voltage

 DESCRIPTION (provided by applicant): It is well established that altered sarcoplasmic reticulum (SR) Ca handling plays a key role in HF pathogenesis. Whereas altered post-translational modifications (PTM) of the SR Ca release channel/ ryanodine receptor type- 2 (RyR2) have been linked to HF development, it remains highly controversial which kinases and phosphatases underlie these disease-associated changes. RyR2 hyper-phosphorylation can be caused by increased activity of protein kinase A (PKA) and Ca/calmodulin-dependent protein kinase II (CaMKII). However, there remains significant controversy about the mechanisms underlying altered phosphorylation of RyR2 in HF. We have identified a novel kinase within the RyR2 macromolecular complex, known as `striated muscle preferentially expressed gene' (SPEG). Our preliminary data show that SPEG phosphorylates a novel phosphorylation site on RyR2, S2811. In addition, our data suggest that SPEG levels are downregulated in patients and mice with congestive heart failure. Our long-term goal is to define the molecular and cellular mechanisms by which SEPG regulates RyR2 and intracellular Ca handling in normal and failing hearts. The overall hypothesis is that SPEG phosphorylates a novel S2811 residue on RyR2, which modulates RyR2 activity and intracellular Ca handling in cardiac myocytes. Specific aim (1) will determine how SPEG binds to RyR2 and how SPEG modifies intracellular Ca handling. Specific aim (2) will assess the role of SPEG modulation of RyR2 in heart failure. Specific aim (3) will determine the role of SPEG-mediated phosphorylation of S2811 on RyR2 in normal and failing hearts. Significance: Heart failure (HF) is a deadly and costly disease affecting 5.7 millin people in the US alone, and a leading cause of hospitalization for those >65 years of age. A better understanding of the molecular mechanisms underlying abnormal RyR2 function in HF could lead to new pharmacological strategies.

 描述（由申请方提供）：已明确，肌浆网（SR）钙处理改变在HF发病机制中起关键作用。尽管SR Ca释放通道/ ryanodine受体2型（RyR 2）的翻译后修饰（PTM）改变与HF的发生有关，但哪些激酶和磷酸酶是这些疾病相关变化的基础仍然存在高度争议。RyR 2过度磷酸化可由蛋白激酶A（PKA）和Ca/钙调蛋白依赖性蛋白激酶II（CaMKII）的活性增加引起。然而，关于HF中RyR 2磷酸化改变的机制仍然存在重大争议。我们已经确定了一种新的激酶内RyR 2大分子复合物，被称为“横纹肌优先表达基因”（SPEG）。我们的初步数据表明，SPEG磷酸化RyR 2上的一个新的磷酸化位点，S2811。此外，我们的数据表明，在充血性心力衰竭患者和小鼠中，SPEG水平下调。我们的长期目标是确定SEPG调节RyR 2和细胞内Ca处理在正常和衰竭心脏的分子和细胞机制。总体假设是SPEG磷酸化RyR 2上的一个新的S2811残基，其调节RyR 2活性和心肌细胞中的细胞内Ca处理。具体目标（1）将确定SPEG如何与RyR 2结合以及SPEG如何改变细胞内Ca处理。具体目标（2）将评估RyR 2的SPEG调节在心力衰竭中的作用。具体目标（3）将确定在正常和衰竭心脏中，S2811对RyR 2的SPEG介导的磷酸化的作用。重要性：心力衰竭（HF）是一种致命且昂贵的疾病，仅在美国就影响570万人，并且是>65岁患者住院的主要原因。更好地了解HF中RyR 2功能异常的分子机制可能会导致新的药理学策略。