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Examining role of splicing factor mutations in myelodysplastic syndrome (PQ11)

检查剪接因子突变在骨髓增生异常综合征 (PQ11) 中的作用

基本信息

批准号：
8527752
负责人：
Shalini Sharma
金额：
$ 16.48万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-15 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8527752
关键词：
Affect Apoptosis Biochemical Blast Cell Blood Cells Bone Marrow CD34 gene Cell Cycle Progression Cell Cycle Regulation Cells Chromosome abnormality Chronic Lymphocytic Leukemia Chronic Myelomonocytic Leukemia Colorectal Cancer Complex Core Protein Defect Development Diagnosis Differentiation and Growth Disease Disease Outcome Disease Progression Dysmyelopoietic Syndromes Dysplasia Event Excision Exons Frequencies Gene Expression Profile Gene Mutation Generations Goals Growth Growth and Development function Hematopoiesis Hematopoietic Human Induced Mutation Introns Knowledge Lead Link Malignant Neoplasms Malignant neoplasm of pancreas Mediating Messenger RNA Mitosis Molecular Mutation Myeloproliferative disease Pathogenesis Patients Pattern Point Mutation Prognostic Marker Property Protein Splicing Proteins RNA Interference RNA Sequences RNA Splicing Recurrence Refractory Refractory Anemia with Excess Blasts in Transformation Refractory Anemia with Ringed Sideroblasts Refractory anaemia with excess blasts Refractory anemias Ribonucleoproteins Ringed Sideroblast Role Site Small Nuclear Ribonucleoproteins Somatic Mutation Spliceosomes Stem cells Techniques Testing Transcript U2 Small Nuclear Ribonucleoprotein Umbilical Cord Blood United States base cytopenia density disease phenotype exome genome-wide insight mRNA Precursor malignant breast neoplasm melanoma mutant new therapeutic target protein function stem transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): Regulated splicing of the cellular transcriptome is essential for normal growth and development. Aberrant expression of splicing patterns is linked to cancers and many other diseases. These abnormal splicing patterns may arise from mutations in pre-mRNA splice sites or in the protein components of the splicing machinery. Recent exome analysis of myelodysplastic syndrome (MDS) patients indicates a link between point mutations in core proteins of the splicing machinery and disease pathogenesis. Somatic mutations in eight splicing proteins were found to be recurrent in MDS cases. This association makes it essential to understand the mechanisms by which these spliceosomal proteins mutations lead to a disease phenotype. We hypothesize that the pathogenic effects of MDS mutations in splicing factors are mediated through changes in their splicing functions. The MDS mutations affect the normal functions of these proteins, resulting in generation of abnormal splicing patterns of transcripts that are important in hematopoiesis. This causes aberrant growth control in HSPCs. The goal of this project is to determine the molecular effects of MDS mutations on splicing factor function and to identify genome-wide splicing aberrations they induce during hematopoiesis that contribute to MDS pathogenesis. We will focus on mutations in SF3B1 and U2AF35 proteins. Distribution of mutations in these two proteins differs amongst the MDS types. SF3B1 mutations are frequent in MDS types that are characterized by ringed sideroblasts (RS), whereas U2AF35 mutations occur in forms of MDS without RS. This mutually exclusive occurrence and their very specific disease outcomes indicate differences in their pathogenic effect and likely distinct mechanisms of disease progression. We will use advanced high density RNA sequencing techniques to identify the MDS mutation induced aberrations in splicing profile of hematopoietic stem/progenitor cells. Effect of these mutations on normal proliferation and differentiation of HSPCs will be determined. Mechanisms underlying aberrant splicing will be determined by defining the MDS mutation- induced changes in U2AF35 and SF3B1 splicing functions using biochemical techniques. Using this approach we expect to define specific splicing events controlled by U2AF35 and SF3B1 during normal hematopoiesis and then elucidates how their mutation contributes to MDS pathogenesis.

描述（由申请人提供）：细胞转录组的调节剪接对正常生长和发育至关重要。剪接模式的异常表达与癌症和许多其他疾病有关。这些异常的剪接模式可能是由前mrna剪接位点的突变或剪接机制的蛋白质成分的突变引起的。最近对骨髓增生异常综合征（MDS）患者的外显子组分析表明，剪接机制核心蛋白的点突变与疾病发病机制之间存在联系。8种剪接蛋白的体细胞突变在MDS病例中反复出现。这种关联使得理解这些剪接体蛋白突变导致疾病表型的机制至关重要。我们假设MDS剪接因子突变的致病作用是通过剪接功能的改变介导的。MDS突变会影响这些蛋白的正常功能，导致在造血过程中重要的转录物的异常剪接模式的产生。这导致HSPCs异常生长控制。该项目的目标是确定MDS突变对剪接因子功能的分子效应，并确定它们在造血过程中诱导的全基因组剪接畸变，从而促进MDS的发病机制。我们将重点关注SF3B1和U2AF35蛋白的突变。这两种蛋白的突变分布在不同的MDS类型中是不同的。SF3B1突变在以环状铁母细胞（RS）为特征的MDS类型中很常见，而U2AF35突变发生在不含RS的MDS类型中。这种互斥的发生及其非常特定的疾病结局表明，它们的致病作用和疾病进展的可能不同机制存在差异。我们将使用先进的高密度RNA测序技术来鉴定MDS突变诱导的造血干细胞/祖细胞剪接谱畸变。这些突变对HSPCs正常增殖和分化的影响将被确定。通过使用生化技术定义MDS突变诱导的U2AF35和SF3B1剪接功能的变化，将确定异常剪接的机制。使用这种方法，我们期望定义正常造血过程中由U2AF35和SF3B1控制的特定剪接事件，然后阐明它们的突变如何促进MDS发病。