PICOT and Cardiac Hypertrophy

PICOT 和心脏肥大

• 批准号: 7565957
• 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/7565957
• 关键词: Acute; Adenoviruses; Adult; Affinity Chromatography; Binding; Binding Proteins; Biological Assay; Cardiac; Cardiac Myocytes; Chimeric Proteins; Chronic; Complex; Congestive Heart Failure; Development; Dominant-Negative Mutation; Down-Regulation; Endothelin-1; Failure; Feedback; Gene Transfer; Genetic Models; Goals; Heart; Heart Hypertrophy; Heart failure; Hypertrophy; In Vitro; Ischemic Preconditioning; Isoenzymes; Mediating; Molecular; Muscle Cells; Neonatal; Operative Surgical Procedures; Phenylephrine; Physiological; Protein Isoforms; Protein Kinase C; Protein Kinase C Inhibitor; 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; constriction; design; hypertensive heart disease; in vivo; novel strategies; novel therapeutics; overexpression; pressure; programs; protein complex; 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途径已与心脏肥大的发展和肥大的发展有关，其中蛋白激酶C（PKC）信号传导途径是该建议的重点。在初步研究中，我们发现1）PKC结合蛋白PICOT（硫氧还蛋白的PKC-LnterActing Cousin）在心脏肥大的发展过程中被上调，而2）在新生儿大鼠脑室心肌（NRVM）和Rat Hearts中强迫PICOT表达了Cardialty the Cardiact hearvery的发展。这些结果表明，PICOT是心脏肥大的关键负反馈调节剂，因此提供了阻止心脏肥大和心力衰竭发展的新型策略。该提案的目的是定义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的啮齿动物模型中的有益作用。我们提出以下特定目的：1）定义PICOT活性的分子机制及其与其他PKC同工型的相互作用，2）通过蛋白质组学方法表征PICOT复合物，以及3）定义picot在体内心脏中PICOT过度表达的生理后果。实现这三个特定目标将对通过抑制PKC活性施加的心脏肥大的负面反馈机制有更深入的了解，并将允许设计新颖的治疗策略来管理心脏肥大和心力衰竭。