X-linked Dyskeratosis Congenita and ribosomal frameshifting

X连锁先天性角化不良和核糖体移码

• 批准号: 8894573
• 负责人: Jonathan D Dinman
• 金额: $ 61.73万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8894573
• 关键词: Ablation; Address; Affect; Affinity; Binding Proteins; Biological Markers; Biological Process; Candidate Disease Gene; Cells; Collaborations; Data; Databases; Defect; Development; Diagnostic; Disease; Exhibits; Foundations; Functional disorder; Gap Junctions; Gene Expression; Gene Targeting; Genes; Genetic; Global Change; Health; Hematopoietic; Hematopoietic stem cells; Human; Impairment; Inherited; Laboratories; Ligands; Link; Malignant Neoplasms; Mediating; Medical; Messenger RNA; MicroRNAs; Modification; Molecular; Mus; Mutation; Nonsense Codon; Pancytopenia; Pathogenesis; Pathway interactions; Patients; Process; Prognostic Marker; Protein Biosynthesis; Proteins; Pseudouridine; Publishing; RNA Splicing; Regulator Genes; Research; Resolution; Ribosomal Frameshifting; Ribosomal RNA; Ribosomes; Role; Signal Transduction; Syndrome; System; Telomere Maintenance; Telomere Shortening; Telomeric Repeat Binding Protein 2; Testing; Therapeutic; Therapeutic Intervention; Transfer RNA; Translating; Translations; Uridine; Validation; Work; X-Linked Dyskeratosis Congenita; Yeast Model System; Yeasts; base; bone marrow failure syndrome; cis acting element; induced pluripotent stem cell; mRNA Decay; mRNA Stability; mRNA Transcript Degradation; mouse model; novel; novel diagnostics; novel strategies; novel therapeutics; programs; protein expression; research study; stem cell differentiation; synthetic protein; transcriptome sequencing

DESCRIPTION (provided by applicant): Abnormalities in ribosome function that are implicated in both congenital and acquired bone marrow failure syndromes in humans are classified under the broad umbrella of ribosomopathies. A recent collaboration between our two laboratories has initiated a completely new avenue of research by establishing an evolutionarily conserved role for ribosome modifications mediated by the pseudouridine synthase dyskerin in specific aspects of translation control. The functional role of pseudouridine (�) modifications is of great medical importance as mutations in DKC1, the gene encoding for dyskerin, are found in a number of diseases including X-linked dyskeratosis congenita (X-DC), Hoyeraal-Hreidarsson syndrome, and numerous cancers. Importantly, our published work has identified that the decreased affinity of rRNA � defective ribosomes for tRNAs results in increased rates of programmed -1 ribosomal frameshifting (-1 PRF), a molecular mechanism that is emerging as an important regulator of gene expression. This proposal seeks to test the hypothesis that global changes in -1 PRF affect the expression of specific subsets of mRNAs encoding key hematopoietic factors, that may contributing to some of the pathological features associated with X- DC. Support for this hypothesis is evident from our extensive published and unpublished findings showing that increased rates of -1 PRF promotes rapid degradation of specific mRNAs through the Nonsense-Mediated mRNA Decay (NMD) pathway. Furthermore, we have demonstrated that rRNA � levels are impaired in hematopoietic cells from X-DC patients harboring distinct DKC1 mutations. Importantly, our preliminary and published data also suggest that one important functional class of mRNAs involved in telomere maintenance is regulated by this mechanism in both yeast and human cells and is disrupted in X-DC patients, thus linking rRNA � defects and telomere shortening. By utilizing X-DC as a disease paradigm and combining three model systems, yeast, mouse and humans, in this proposal we will extend our novel findings and identify the repertoire of mRNAs that underlie bone marrow failure associated with ribosome dysfunction and determine the therapeutic potential of inhibiting NMD and -1 PRF in X-DC. Aim 1 of this proposal seeks to identify the repertoire of mRNAs whose expression is affected by rRNA � defects in yeast, mouse and human cells using two complementary approaches. Aim 2 will determine the mechanisms through which impaired rRNA � alters expression of -1 PRF containing mRNAs. Aim 3 is oriented towards determining the therapeutic potential of targeting NMD and -1 PRF in X-DC. By the end of the proposed studies, we will have 1) established a new paradigm for understanding ribosomopathies, 2) identified specific genes that can be used as biomarkers and targeted for therapeutic intervention, and 3) explored novel approaches to treat this class of diseases.

描述（由适用提供）：在人类的先天性和可靠的骨髓衰竭综合症中实现的核糖体功能异常，在核糖体病的广泛伞下分类。我们两个实验室之间的最新合作通过在翻译控制的特定方面建立了由假硫胺合酶Dyskerin介导的核糖体修饰的进化作用，从而启动了全新的研究途径。假氨酸修饰（）修饰的功能作用非常重要，因为DKC1中的突变是dydyskerin的基因，在许多疾病中都发现了许多疾病，包括X连锁性障碍性脑（X-DC），Hoyeral-Hyeral-Hreidarsson综合征以及许多Cancers。重要的是，我们已发表的工作已经确定RRNA的亲和力降低了核糖体对TRNA的有缺陷的核糖体导致编程的-1核糖体Frameshifting（-1 PRF）的速率提高，这是一种分子机制，这是一种作为基因表达的重要调节剂的分子机制。该提案旨在检验以下假设：-1 prf的全球变化影响编码关键造血因素的mRNA特定子集的表达，这可能有助于与X -DC相关的某些病理特征。我们广泛发表和未发表的发现证明了对这一假设的支持，表明-1 PRF的速率提高可通过胡说八道介导的mRNA Decay（NMD）途径促进特定mRNA的快速降解。此外，我们已经证明，来自具有不同DKC1突变的X-DC患者的造血细胞中RRNA水平受损。重要的是，我们的初步和发布的数据还表明，涉及端粒维持的mRNA的一个重要功能类别受到酵母和人类细胞中这种机制的调节，并在X-DC患者中被破坏，从而将RRNA缺陷和端粒缩短联系起来。通过利用X-DC作为疾病范式并结合了三个模型系统，即酵母，小鼠和人类，在此提案中，我们将扩展我们的新发现，并确定与核糖体功能障碍相关的骨髓失败的mRNA曲目，并确定抑制NMD和-1 PRF在X-DC中的治疗潜力。该提案的目标1旨在通过两种完整的方法来确定其表达受酵母，小鼠和人类细胞缺陷的表达影响的mRNA的曲目。 AIM 2将确定rRNA受损的机制，以改变含有mRNA的-1 pRF的表达。 AIM 3面向确定靶向NMD的治疗潜力和X -DC中-1 PRF的治疗潜力。到拟议的研究结束时，我们将有1）建立一个新的范式来理解核糖瘤病，2）鉴定出可以用作生物标志物并针对治疗干预的特定基因，以及3）探讨了治疗这种疾病的新方法。