Investigating and targeting the translational landscape of DBA

(请保存在Word中，不要保存为PDF) 在此输入文本，它是您的应用程序的新摘要信息。此部分不得超过30行文本。 在核糖体疾病中，核糖体成分的干扰表达会导致组织特有的表型，如四肢和颅面部缺陷以及骨髓衰竭。核糖体疾病的一个关键例子是钻石黑扇贫血(DBA)，它导致红系特有的疾病表现。核糖体是一种普遍存在的细胞机器，它的突变导致了这种组织选择性的表现，这是什么原因仍然是一个谜。我们的初步数据有力地支持了翻译功能障碍可能在疾病发病机制中的作用。特别是，我们的发现表明，核糖体蛋白(RP)单倍体不足对基因表达的翻译特异性可能源于一条中间途径，即p53-4EBP1-eIF4E轴，该轴被激活并将RP单倍体不足与帽依赖翻译中的选择性变化联系起来，即具有结构性5‘UTRs的mRNAs，需要eIF4A解旋酶活性或具有特定的序列元件。这一初步数据有力地支持了在造血室内检查翻译控制和蛋白质合成的基本原理，这是以前无法解决的问题，限制了我们对DBA发病机制的理解。在目标1中，我们将描述4EBP1在控制转录特异性翻译控制中的功能，这可能是DBA发病的基础。特别是，我们将确定4EBP1介导的长的、结构化的5‘UTRs的翻译是否在RP单倍体不足时受损，并可能是DBA发病的基础。在目标2中，我们将表征一种新的小分子，它上调一般的蛋白质合成，作为恢复DBA翻译景观的一种手段。特别是，我们将定义我们已经在大型化学筛选中确定的半合成大环内酯类抗生素阿奇霉素是如何作为翻译激活剂发挥作用的。我们还将在人类干细胞模型中测试阿奇霉素在挽救DBA发病机制中的作用。总而言之，这项提议有可能改变我们对整个人类疾病类别的理解和治疗。

(PLEASE KEEP IN WORD, DO NOT PDF) Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. In ribosomopathies, perturbed expression of ribosome components leads to tissue-specific phenotypes, such as limb and craniofacial defects as well as bone marrow failure. A key example of a ribosomopathy is Diamond Blackfan Anemia (DBA) which results in an erythroid-specific disease manifestation. What accounts for such tissue-selective manifestations as a result of mutations in the ribosome, a ubiquitous cellular machine, has remained a mystery. Our preliminary data strongly support that translational dysfunction may contribute to disease pathogenesis. In particular, our findings show that translational specificity to gene expression upon ribosomal protein (RP) haploinsufficiency may arise from an intermediary pathway, the p53-4EBP1-eIF4E axis, which becomes activated and links RP haploinsufficiency to selective changes in cap-dependent translation, namely mRNAs with structured 5’UTRs that require eIF4A helicase activity or that have a specific sequence element. This preliminary data strongly supports the rationale to examine translational control and protein synthesis within the hematopoietic compartment, which has been previously unattainable to resolve and has limited our understanding of DBA pathogenesis. In Aim 1, we will delineate the function of 4EBP1 in controlling transcript-specific translational control that may underlie DBA pathogenesis. In particular, we will define whether 4EBP1 mediated translation of long, structured 5’UTRs is impaired upon RP haploinsufficiency and may underlie DBA pathogenesis. In Aim 2, we will characterize a novel small molecule that upregulates general protein synthesis as a means for restoring the translational landscape of DBA. In particular, we will define how a semi-synthetic macrolide antibiotic, Azithromycin, that we have already identified in a large chemical screen acts as a translation activator. We will also test the effects of Azithromycin in rescuing the pathogenesis of DBA in human stem cell models of the disease. Together, this proposal holds the potential to transform our understanding and treatment of an entire class of human diseases.