NPM1 regulation of 2'-O-methylation in hematopoiesis and bone marrow failure disorder

NPM1 对造血和骨髓衰竭疾病中 2-O-甲基化的调节

基本信息

批准号：
9767117
负责人：
John Clohessy
金额：
$ 40.83万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-07 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9767117
关键词：
Acute Adult Aplastic Anemia Apoptosis Biochemical Biogenesis Bone Development Categories Cell Compartmentation Cell Cycle Cell Maintenance Cells Characteristics Clinical Complex Congenital Abnormality DNA Sequence Alteration Data Defect Development Diamond-Blackfan anemia Disease Dyskeratosis Congenita Dysmyelopoietic Syndromes Event Gene Mutation Genes Genetic Genetic Transcription Genetically Engineered Mouse Germ Lines Germ-Line Mutation Hematological Disease Hematopoiesis Hematopoietic Hematopoietic System Hematopoietic stem cells Homeostasis Hydrogen Bonding In Vitro Inherited Internal Ribosome Entry Site Knock-in Mouse Lesion Link Malignant Neoplasms Mediating Mediator of activation protein Methylation Modification Molecular Mus Mutation NPM1 gene Nuclear Nucleolar Proteins Nucleotides Pancytopenia Pathogenesis Pathogenicity Pathway interactions Patients Phenotype Play Predisposition Process Proteins Pseudouridine RNA RNA Binding RNA Processing RNA methylation Regulation Ribonucleoproteins Ribosomal RNA Ribosomes Role Seminal Small Nucleolar RNA Small Nucleolar Ribonucleoproteins Stem cells Structure Translations Uridine biological adaptation to stress human disease in vivo in vivo Model mouse model mutant novel nucleophosmin patient population response

项目摘要

1R01 DK115536-01 revised Inherited bone marrow failure disorders (BMFDs) represent a distinct category of hematopoietic disorders that are driven by genetic mutation. Within these disorders, a distinct set of genes has already been identified that contribute to a sub-set of BMFDs known as ribosomopathies. Ribosomopathies harbor mutation to genes playing a critical role in ribosomal processing and ribosome biogenesis. We previously established the DKC1 gene as a ribosomopathy gene through its ability to regulate proper translation as a result of its function to convert uridine residues on ribosomal RNAs (rRNAs) to pseudouridine. Exciting, preliminary data from our lab now demonstrates that another post-transcriptional modification of rRNAs, 2’-O-methylation (2’-O-Me), also contribute to proper regulation of ribosome function. Our data reveal that specific C/D-box small nucleolar RNAs (snoRNAs) controls proper IRES-dependent translation of major cell cycle and apoptosis genes. In vivo, disruption of 2’-O-Me in adult mouse hematopoietic stem cell (HSC) compartment results in features characteristic of ribosomopathies such as defects in stem cell maintenance due to exit from quiescence, apoptosis, and myelodysplastic bone marrow failure. Importantly, we identify novel germ line mutations dyskeratosis congenita (DC) patients related to function of C/D box snoRNAs. Thus, our preliminary findings provide direct genetic evidence for the critical role ribosome specialization through rRNA 2’-O-Me, as well as in the pathogenesis of multiple disease states through aberrant HSC and ribosome function. In order to better understand the role and function 2’-O-Me, we propose to (1) study the molecular and cellular pathways that are impacted by 2’-O-Me and which contribute to the process of bone marrow failure, (2) determine the in vivo significance of normal ribosome function for hematopoiesis, and of novel DC mutations identified through development of genetically engineered mouse models, and (3) evaluate the extent to which genes involved in the biochemical complexes that catalyzes 2’-O-Me may be altered in BMFDs, and to determine if additional novel pathogenic mutations targeting the process of rRNA methylation, including snoRNAs, exist in BMFDs. Together these data will further facilitate our understanding of ribosomopathies, and help uncover how essential regulation of the ribosome, through rRNA modification, contributes to normal and aberrant hematopoiesis.

1R01 DK115536-01修订骨髓衰竭疾病（BMFDS）ESE疾病已经有助于核糖体病变的核糖体病变的BMFDS的副群。核糖体RNA（RRNA）上的尿苷残基的ATS功能E.我们实验室的初步数据令人兴奋，证明了RRNA的转录修饰，以适当调节我们的数据，以使我们的数据对特定的C/D -box小核核心RNAS持续发展。（SNORNAS）控制主要循环和凋亡基因的适当依赖IRES的翻译。骨髓衰竭。和核糖体功能。正常核糖体功能对造血的重要性，以及通过开发遗传引擎小鼠模型而变得柔和的新型DC的重要性，并且（3）评估催化2'-O-O-O-O-ME的生物化学复合物的程度可能会改变BMFDS，并确定是否可以改变靶向rRNA甲基化过程的其他新型致病突变（包括snoRNA）存在于BMFD中，并有助于发现核糖体的基本调节，通过RRNA修饰，有助于正常的异常造血。