BEX1 and the control of protein translation in cardiac hypertrophy

摘要 心脏肥大和心力衰竭是一个日益严重的医学和社会问题。目前的医学治疗是 不足以修复心脏只是延缓死亡心肌肥厚是由增加的 心肌细胞中特异性蛋白质的合成。虽然在这方面取得了重大进展， 了解肥大特异性基因表达，现在很清楚，蛋白质表达水平不 总是反映相应基因的转录速率。查明各种机制， 调节蛋白质翻译提供了另一种通过控制蛋白质合成来治疗疾病的关键策略， 选择直接导致心脏肥大的蛋白质。在本提案中，我们将研究BEX 1 在心脏中作为应激刺激期间的翻译控制的新调节剂发挥作用。我们将BEX 1鉴定为 一种在心力衰竭中上调的因子，然后与蛋白质相关分子相互作用， 翻译.我们假设BEX 1是一种新的心肌肥大和适应应激的调节因子 通过对选择的蛋白质的翻译控制，这些蛋白质更接近于参与生长反应。 我们将通过以下目的来验证我们的假设：（1）确定BEX 1在心脏中的作用， 肥大和向体内衰竭转变。(2)为了确定BEX 1在调节转录中的作用， 通过与RPL 22和RNA解旋酶DDX 1和DDX 3x结合，(3)识别 肥大过程中转录后水平控制的mRNA，以及BEX 1在肥大中的作用 调节这个过程。研究提案的最初部分将在杰弗里博士的实验室进行 Molkentin是一位世界著名的心脏研究者，他使用遗传小鼠研究心脏肥大， 模型在这个实验中，我将通过使用BEX 1-null和BEX 1-null来解决BEX 1在心脏中的体内作用。 我将开始研究BEX 1控制BEX 1基因翻译的机制， 特定蛋白质重要的是，除了阐明BEX 1调节翻译的机制外， 在应激刺激后（目标1和2），目前的建议将阐明转录之间的解偶联， 和翻译，并将导致这些mRNA的鉴定， 在肥大期间翻译（目的3）。因此，新的途径和靶向机制将被发现 并将在未来几年推动我的独立研究项目。

Abstract Cardiac hypertrophy and heart failure are a growing medical and social problem. Current medical therapies are insufficient to repair the heart and merely postpone death. Cardiac hypertrophy is mediated by increased synthesis of specific proteins in cardiomyocytes. Although significant progress has been made in understanding hypertrophy-specific gene expression, it is now clear that protein expression levels do not always reflect the rate of transcription of the corresponding genes. The identification of mechanisms that regulate protein translation offers another critical strategy for treating disease by controlling protein synthesis of select proteins that directly underlie cardiac hypertrophy. In this proposal we will examine the role that BEX1 plays in the heart as a novel regulator of translational control during stress stimulation. We identified BEX1 as a factor that is upregulated in heart failure where it then interacts with molecules implicated in protein translation. We hypothesize that BEX1 is a novel regulator of cardiac hypertrophy and adaptation to stress through the translational control of selected proteins that are more proximally involved in the growth response. We will test our hypothesis by carrying out the following aims: (1) To determine the role of BEX1 in cardiac hypertrophy and transition to failure in vivo. (2) To determine the role of BEX1 in modulating the translation of specific mRNAs through association with RPL22 and RNA helicases DDX1 and DDX3x. (3) To identify the mRNAs that are controlled at a post-transcriptional level during hypertrophy, and the role of BEX1 in modulating this process. The initial part of the research proposal will be carried out in the lab of Dr. Jeffery Molkentin, a world-renowned cardiac researcher who studies cardiac hypertrophy using genetic mouse models. In this lab, I will address the in vivo role of BEX1 in the heart by using BEX1-null and BEX1- overexpressing mice and I will start addressing the mechanism by which BEX1 controls the translation of specific proteins. Importantly, in addition to elucidating the mechanism whereby BEX1 regulates translation after stress stimulation (aims 1 and 2), the current proposal will elucidate the uncoupling between transcription and translation in cardiomyocytes and will lead to the identification of those mRNAs that are differentially translated during hypertrophy (aim 3). Therefore, novel pathways and targeting mechanisms will be uncovered and will drive my independent research program for years to come.