Investigating and targeting the translational landscape of DBA

调查并瞄准 DBA 的转化前景

基本信息

批准号：
10867969
负责人：
Maria Barna
金额：
$ 15万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-15 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10867969
关键词：
5&apos Untranslated Regions Address Adrenal Cortex Hormones Affect Antibiotics Apoptosis Azithromycin Biogenesis Bone marrow failure Cell Cycle Arrest Cells Characteristics Chemicals Congenital Abnormality Craniofacial Abnormalities Data Defect Development Diamond-Blackfan anemia Digit structure Disease Disease model Elements Erythroid FDA approved Failure Functional disorder Gene Expression Hematopoietic Impairment Knowledge Life Limb structure Link Macrolides Mediating Messenger RNA Molecular Mutation Pathogenesis Pathologic Pathway interactions Pharmacotherapy Phenotype Prednisone Protein Biosynthesis RNA Recommendation Reporter Ribosomal Proteins Ribosomes Role Specificity Stress Structure TP53 gene Technology Testing Text Therapeutic Therapeutic Agents Tissues Transcript Transfection Translational Regulation Translations clinical phenotype clinically relevant craniofacial disease phenotype efficacy testing erythroid differentiation helicase high throughput screening human disease human stem cells in vivo inhibitor molecular phenotype mouse model novel novel therapeutics ribosome profiling ribosomopathy small molecule stem cell model transcription factor translatome

项目摘要

(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.

（请以 WORD 形式保存，请勿以 PDF 形式保存）在此输入您的申请的新摘要信息的文本。此部分的文本长度不得超过 30 行。在核糖体病中，核糖体成分的表达紊乱会导致组织特异性表型，例如肢体和颅面缺陷以及骨髓衰竭，核糖体病的一个重要例子是钻石黑扇贫血症 (DBA)，它会导致红细胞特异性疾病表现。强核糖体（一种普遍存在的细胞机器）的突变导致这种组织选择性表现的原因仍然是一个谜，我们的初步数据支持这一点。特别是，我们的研究结果表明，核糖体蛋白（RP）单倍体不足时基因表达的翻译特异性可能源于中间途径，即 p53-4EBP1-eIF4E 轴，该轴被激活并将 RP 单倍体不足与帽子依赖性翻译的选择性变化，即具有需要 eIF4A 解旋酶活性或具有特定序列元件的结构化 5'UTR 的 mRNA。强烈支持检查造血室内的翻译控制和蛋白质合成的基本原理，这一点以前无法解决，并且限制了我们对 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。特别是，我们将确定 4EBP1 介导的长结构 5'UTR 翻译是否会因 RP 单倍体不足而受损。在目标 2 中，我们将描述一种上调一般蛋白质合成的新型小分子，作为恢复 DBA 翻译景观的方法，特别是，我们将定义我们拥有的半合成大环内酯抗生素阿奇霉素。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。总之，这项提议有可能改变我们对整个人类疾病的理解和治疗。