BEX1 and the control of protein translation in cardiac hypertrophy

描述（由申请人提供）：心脏肥大和心力衰竭是一个日益严重的医学和社会问题。目前的医学疗法不足以修复心脏，只能推迟死亡。心肌肥大是由心肌细胞中特定蛋白质合成增加介导的。虽然在理解肥大特异性基因表达方面取得了重大进展，但现在清楚的是，蛋白质表达水平并不总是反映相应基因的转录速率。对调节蛋白质翻译的机制的鉴定为通过控制直接导致心脏肥大的选择蛋白质的蛋白质合成来治疗疾病提供了另一种关键策略。在这个提议中，我们将研究BEX 1在心脏中作为应激刺激期间翻译控制的新型调节剂所起的作用。我们将BEX 1确定为一个上调的因子， 在心力衰竭中，它与蛋白质翻译中涉及的分子相互作用。我们假设BEX 1是一种新的调节心脏肥大和适应压力，通过翻译控制选定的蛋白质，更接近参与生长反应。我们将通过以下目的来验证我们的假设：（1）确定BEX 1在体内心脏肥大和向衰竭转变中的作用。(2)确定BEX 1通过与RPL 22和RNA解旋酶DDX 1和DDX 3x结合在调节特定mRNA翻译中的作用。(3)确定肥大过程中在转录后水平控制的mRNA，以及BEX 1在调节这一过程中的作用。该研究计划的最初部分将在Jeffey Molkentin博士的实验室进行，他是一位世界知名的心脏研究人员，使用遗传小鼠模型研究心脏肥大。在这个实验中，我将通过使用BEX 1-null和BEX 1- overexpressing小鼠来解决BEX 1在心脏中的体内作用，我将开始解决BEX 1控制特定蛋白质翻译的机制。重要的是，除了阐明应激刺激后BEX 1调节翻译的机制（目的1和2）外，目前的提议将阐明心肌细胞中转录和翻译之间的解偶联，并将导致鉴定在肥大期间差异翻译的那些mRNA（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计划。

DESCRIPTION (provided by applicant): 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. Jeffey 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 mechanis 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.