PICOT and Cardiac Hypertrophy

PICOT 和心脏肥大

• 批准号: 7171819
• 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/7171819
• 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）：压力超负荷诱导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参与了心肌肥厚的发生和发展，其中蛋白激酶C（PKC）信号通路是本研究的重点。在初步研究中，我们发现：1）PKC结合蛋白PICOT（硫氧还蛋白的PKC相互作用表亲）在心肌肥厚的发展过程中上调; 2）PICOT在新生大鼠心室肌细胞（NRVM）和大鼠心脏中的增强表达消除了心肌肥厚的发展。这些结果表明，PICOT是心脏肥大的关键负反馈调节剂，从而提供了一种新的策略来阻断心脏肥大和心力衰竭的发展。该提案的目的是确定PICOT抑制PKC的分子机制，并评估PICOT过表达在心脏肥大和心力衰竭啮齿动物模型中的有益作用。我们提出了以下具体目标：1）定义PICOT活性及其与其他PKC亚型相互作用的分子机制，2）通过蛋白质组学方法表征PICOT复合物，3）定义体内心脏中PICOT过表达的生理后果。实现这三个特定的目标将提供一个更好的理解的负反馈机制的心脏肥大所施加的抑制PKC活性，并将允许设计新的治疗策略，用于管理心脏肥大和心力衰竭。