PICOT and Cardiac Hypertrophy

PICOT 和心脏肥大

• 批准号: 7450757
• 负责人: Roger J. Hajjar
• 金额: $ 41.15万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2011-01-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7450757
• 关键词: Acute; Adenoviruses; Adult; Affinity Chromatography; Binding; Binding Proteins; Biological Assay; Cardiac; Cardiac Myocytes; Chimeric Proteins; Chronic; Complex; Congestive Heart Failure; Constriction procedure; Development; Dominant-Negative Mutation; Down-Regulation; Endothelin-1; Failure; Feedback; Gene Transfer; Genetic Models; Glutathione S-Transferase; Goals; Heart; Heart Hypertrophy; Heart failure; Hypertrophy; In Vitro; Ischemic Preconditioning; Isoenzymes; Mediating; Molecular; Muscle Cells; Neonatal; Numbers; Operative Surgical Procedures; Phenylephrine; Physiological; Protein Isoforms; Protein Kinase C; Protein Kinase C Inhibitor; Protein Overexpression; Proteins; Proteomics; Rattus; Reagent; Recombinant adeno-associated virus (rAAV); Recombinants; Regulation; Research Personnel; Rodent; Rodent Model; Role; Screening procedure; Signal Pathway; Signal Transduction Pathway; Stimulus; Testing; Thioredoxin; Transfection; Transgenic Mice; Transgenic Organisms; Ventricular; Yeasts; citrate carrier; design; hypertensive heart disease; in vivo; novel strategies; novel therapeutics; pressure; programs; response; yeast two hybrid system

DESCRIPTION (provided by applicant): Pressure overload-induced cardiac hypertrophy is one of the most common causes of heart failure. Many intracellular signal transduction pathways have been implicated in the development of cardiac hypertrophy and the progression of hypertrophy to heart failure, among which the protein kinase C (PKC) signaling pathway is the focus of this proposal. In preliminary studies, we found that 1) a PKC binding protein, PICOT (PKC-lnteracting Cousin Of Thioredoxin), is up-regulated during the development of cardiac hypertrophy and 2) enforced expression of PICOT in the neonatal rat ventricular myocyte (NRVM) and rat hearts abrogates the development of cardiac hypertrophy. These results suggest that PICOT is a key negative feedback regulator of cardiac hypertrophy, and thus provides a novel strategy to block the development of cardiac hypertrophy and heart failure. The goal of this proposal is to define the molecular mechanism of PKC inhibition by PICOT, and to evaluate the beneficial effects of PICOT overexpression in the rodent models of cardiac hypertrophy and heart failure. We propose the following specific aims: 1) Defining the molecular mechanism of PICOT activity and its interactions with other PKC isoforms, 2) Characterizing the PICOT complex by proteomic approaches, and 3) Defining the physiological consequences of PICOT overexpression in the hearts in vivo. Accomplishing these three specific aims will provide a greater understanding of the negative feedback mechanism of cardiac hypertrophy exerted by inhibiting PKC activity, and will allow for the design of novel therapeutic strategies for the management of cardiac hypertrophy and heart failure.

描述（由申请人提供）：压力超负荷引起的心脏肥大是心力衰竭的最常见原因之一。许多细胞内信号转导通路与心脏肥大的发生以及肥厚进展为心力衰竭有关，其中蛋白激酶C（PKC）信号通路是本提案的重点。在初步研究中，我们发现 1) PKC 结合蛋白 PICOT（硫氧还蛋白的 PKC 相互作用表兄弟）在心脏肥大的发展过程中上调，2) PICOT 在新生大鼠心室肌细胞 (NRVM) 和大鼠心脏中的强制表达可消除心脏肥大的发展。这些结果表明 PICOT 是心脏肥大的关键负反馈调节因子，从而提供了一种阻止心脏肥大和心力衰竭发展的新策略。本提案的目的是明确 PICOT 抑制 PKC 的分子机制，并评估 PICOT 过表达在啮齿动物心脏肥大和心力衰竭模型中的有益作用。我们提出以下具体目标：1) 定义 PICOT 活性的分子机制及其与其他 PKC 同种型的相互作用，2) 通过蛋白质组学方法表征 PICOT 复合物，3) 定义 PICOT 在心脏中过度表达的生理后果。实现这三个具体目标将有助于更好地理解抑制 PKC 活性所产生的心脏肥大的负反馈机制，并将有助于设计治疗心脏肥大和心力衰竭的新治疗策略。