BEX1 and the control of protein translation in cardiac hypertrophy

BEX1 和心脏肥大中蛋白质翻译的控制

• 批准号: 8616925
• 负责人: Federica Accornero
• 金额: $ 13.11万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-20 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8616925
• 关键词: Achievement; Address; Adult; Animals; Binding; Brain; Cardiac; Cardiac Myocytes; Carrier Proteins; Cell Nucleus; Cells; Cessation of life; Complex; Cytoplasm; DDX1 gene; Failure; Family; Gene Expression; Genes; Genetic; Genetic Transcription; Growth; Heart; Heart Diseases; Heart Hypertrophy; Heart failure; Hypertrophy; Injury; Knockout Mice; Lead; Literature; Mediating; Mediator of activation protein; Medical; Messenger RNA; Modeling; Molecular; Molecular Profiling; Mus; Myocardial; Null Lymphocytes; Pathologic; Pathology; Pathway interactions; Physiological; Play; Post-Transcriptional Regulation; Process; Protein Biosynthesis; Proteins; Proteomics; RNA Helicase; RNA Transport; Regulation; Reporting; Research; Research Personnel; Research Proposals; Rest; Ribosomal Proteins; Ribosomes; Role; Social Problems; Stress; Testing; Therapeutic; Transcriptional Regulation; Translating; Translations; biological adaptation to stress; disorder control; in vivo; link protein; mouse model; new therapeutic target; novel; novel strategies; overexpression; pressure; programs; prospective; protein expression; repaired; response

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.

摘要 心脏肥厚和心力衰竭是一个日益严重的医学和社会问题。目前的医学疗法是 不足以修复心脏，只是推迟死亡。心肌肥厚是由心肌肥厚引起的 心肌细胞中特定蛋白质的合成。尽管在以下方面取得了重大进展 了解肥大特异的基因表达，现在很明显，蛋白质表达水平不 总是反映相应基因的转录速度。机制的识别 调节蛋白质翻译通过控制蛋白质的合成为治疗疾病提供了另一种关键策略 选择直接导致心肌肥厚的蛋白质。在本提案中，我们将研究BEX1 在应激刺激期间，作为一种新的翻译控制调节器，它在心脏中发挥作用。我们确认BEX1为 一种在心力衰竭中上调的因子，然后与蛋白质中涉及的分子相互作用 翻译。我们推测BEX1是一种新的心肌肥厚和应激适应调节因子 通过对与生长反应更密切相关的选定蛋白质的翻译控制。 我们将通过实现以下目标来验证我们的假设：(1)确定BEX1在心脏中的作用 体内的肥大和向衰竭的过渡。(2)确定BEX1对翻译的调控作用 通过与RPL22和RNA解旋酶DDX1和DDX3X结合而获得特定的mRNAs。(3)识别 在肥厚过程中转录后水平控制的mRNAs，以及BEX1在 调节这一过程。研究计划的最初部分将在杰弗里博士的实验室进行 世界著名的心脏研究员莫尔肯丁利用基因小鼠研究心肌肥厚 模特们。在本实验中，我将通过使用BEX1-Null和BEX1-来说明BEX1在心脏中的活体作用。 过度表达小鼠和我将开始讨论BEX1控制翻译的机制 特定的蛋白质。重要的是，除了阐明BEX1调节翻译的机制 在应激刺激(目标1和2)之后，目前的建议将阐明转录之间的解偶联 和翻译，并将导致识别这些差异的mRNAs 在肥大期间翻译(目标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。