PKC-EHN-PKD signal complex in cardiac remodeling

心脏重塑中的 PKC-EHN-PKD 信号复合体

• 批准号: 7839532
• 负责人: MASAHIKO HOSHIJIMA
• 金额: $ 23.86万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 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 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7839532
• 关键词: Animal Model; Benign; Binding; Cardiac; Cardiac Myocytes; Cell Culture System; Complex; Dilated Cardiomyopathy; Dominant-Negative Mutation; Exercise; Failure; Heart; Heart Hypertrophy; Heart failure; Hypertrophy; Left Ventricular Hypertrophy; Link; Mechanical Stress; Modeling; Molecular; Mus; Muscle; Myocardial Infarction; Myocardium; Outcome Study; Pharmaceutical Preparations; Phosphotransferases; Physiological; Play; Process; Protein Kinase C; Proteins; Pulmonary artery structure; Receptor Signaling; Regulation; Research; Right ventricular structure; Role; Signal Transduction; Stress; Testing; Transgenic Mice; base; calcium-independent protein kinase C; citrate carrier; design; in vivo; mouse model; novel; protein kinase D; receptor coupling; receptors for activated C kinase; response

DESCRIPTION (provided by applicant): Cardiac remodeling is triggered in response to mechanical stress and various neurohumoral factors. We have recently discovered that protein kinase D (PKD), which has been scarcely studied in cardiomyocytes, plays a significant role to regulate cardiac hypertrophy and remodeling in the downstream of Gq-coupling receptor (GqPCR) -protein kinase C (PKC) signaling. Furthermore, we have identified that a muscle restricted PDZ-3LIM protein, ENH1, has a unique function to selectively and directly bind to PKC and PKD and segregate this kinase complex to cardiac Z-disc, which has been thought as a central machinery of mechanical stress signaling. Based on these observations, we hypothesize that the PKCr ENH1-PKD1 complex plays a critical role in the regulation of cardiac hypertrophy and remodeling by integrating GqPCR signaling and mechanical stress signaling. In this proposal, we will test this hypothesis using a combinatory strategy of genetically modified mouse models and in vivo physiological analysis. The research focuses on in vivo analysis of the relationship between the mechanical stress-induced cardiac remodeling and the PKC-ENH1-PKD1 signal complex. Accordingly, our specific aims are: 1) to characterize in vivo activation of PKD in the process of cardiac remodeling in animal models of cardiac hypertrophy and failure, 2) to generate and characterize cardiac transgenic mice with constitutive active and dominant negative mutants of PKD, 3) to test ENH-null hearts and cardiomyocytes to define the physiological roles of ENH in cardiac mechanical stress signaling, and 4) to examine potential downstream target molecules of PKC-ENH-PKD signaling in cardiac remodeling. We anticipate that the outcome of these studies will assist our better understanding of molecular mechanisms that determine the fate of stressed cardiomyocytes and help to design new drug to induce favorable remodeling in diseased hearts.

描述（由申请人提供）：心脏重塑是对机械应力和各种神经体液因素的反应。我们最近发现，蛋白激酶D（PKD），这是很少研究的心肌细胞，发挥了重要作用，在下游的Gq偶联受体（GqPCR）-蛋白激酶C（PKC）信号调节心肌肥厚和重塑。此外，我们已经确定，肌肉限制的PDZ-3LIM蛋白，ENH 1，具有选择性和直接结合到PKC和PKD和分离这种激酶复合物的心脏Z盘，这已被认为是机械应力信号传导的中央机构的独特功能。基于这些观察结果，我们假设PKCr ENH 1-PKD 1复合物通过整合GqPCR信号和机械应力信号在调节心脏肥大和重塑中起关键作用。在这个提议中，我们将使用转基因小鼠模型和体内生理分析的组合策略来测试这一假设。该研究重点是在体内分析机械应力诱导的心脏重塑与PKC-ENH 1-PKD 1信号复合物之间的关系。因此，我们的具体目标是：1）表征在心脏肥大和衰竭的动物模型中心脏重构过程中PKD的体内活化，2）产生和表征具有PKD的组成型活性和显性失活突变体的心脏转基因小鼠，3）测试ENH缺失的心脏和心肌细胞以确定ENH在心脏机械应力信号传导中的生理作用，以及4）检测心脏重构中PKC-ENH-PKD信号传导的潜在下游靶分子。我们预计，这些研究的结果将有助于我们更好地理解决定应激心肌细胞命运的分子机制，并有助于设计新的药物来诱导患病心脏的有利重塑。

项目成果

PKCepsilon-PKD1 signaling complex at Z-discs plays a pivotal role in the cardiac hypertrophy induced by G-protein coupling receptor agonists.

• DOI: 10.1016/j.bbrc.2004.12.128
• 发表时间: 2005-02
• 期刊: Biochemical and biophysical research communications
• 影响因子: 3.1
• 作者: Miki Iwata;A. Maturana;M. Hoshijima;K. Tatematsu;T. Okajima;J. Vandenheede;J. Van Lint;K. Tanizawa;S. Kuroda