PICOT and Cardiac Hypertrophy

描述(申请人提供)：压力超负荷引起的心肌肥厚是心力衰竭最常见的原因之一。许多细胞内信号转导通路参与了心肌肥厚的发生和从肥厚到心力衰竭的进展，其中蛋白激酶C(PKC)信号转导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)在心肌肥厚的发生过程中上调；2)在新生大鼠的心室肌细胞(NRVM)和大鼠心脏中，Picot的表达增强抑制了心肌肥厚的发生。这些结果表明，Picot是心肌肥厚的关键负反馈调节因子，从而为阻断心肌肥厚和心力衰竭的发展提供了一种新的策略。本研究的目的是明确Picot抑制PKC的分子机制，并评价Picot过度表达对心肌肥厚和心力衰竭啮齿动物模型的有利作用。我们提出的具体目标如下：1)明确Picot活性的分子机制及其与其他PKC亚型的相互作用；2)用蛋白质组学方法表征Picot复合体；3)确定在活体心脏中Picot过表达的生理后果。这三个特定目标的实现将有助于更好地理解抑制PKC活性对心肌肥厚的负反馈机制，并将有助于设计新的治疗策略来管理心肌肥厚和心力衰竭。

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.