Synergestic roles of SRSF2 and RUNX1 in blood cell development and pathology

SRSF2 和 RUNX1 在血细胞发育和病理学中的协同作用

• 批准号: 8734415
• 负责人: XIANG-DONG FU
• 金额: $ 46.09万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-16 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8734415
• 关键词: Affect; Alternative Splicing; Animal Model; Basic Science; Biochemical; Biological Assay; Biological Process; Blood Cells; Bone Marrow Cells; Bone Marrow Diseases; CD34 gene; Cell Differentiation process; Cell Proliferation; Cell model; Cells; ChIP-seq; Chemicals; Data; Development; Disease; Disease model; Dysmyelopoietic Syndromes; Event; Failure; Foundations; Frequencies; Functional disorder; Gene Expression; Gene Mutation; Genes; Genetic; Genetic Transcription; Genome; Genomics; Goals; Hematopoiesis; Hematopoietic; Human; Intervention; Large-Scale Sequencing; Lead; Link; Messenger RNA; Molecular; Mutate; Mutation; Pancytopenia; Pathology; Pathway interactions; Patients; Phenotype; Play; Proline; Property; Protein Isoforms; Quality of life; RNA Binding; RNA Splicing; RUNX1 gene; Research; Research Design; Role; Sampling; Series; Site; Stem cells; Sum; Syndrome; Technology; Testing; Transcription Elongation; Transcriptional Activation; Translational Research; Umbilical Cord Blood; base; disease phenotype; effective therapy; experience; gene function; insight; mouse model; mutant; novel; novel therapeutics; outcome forecast; promoter; public health relevance; screening; stem; tool; transcription factor; transcriptome sequencing

DESCRIPTION (provided by applicant): Recent large-scale sequencing efforts have revealed prevalent mutations in splicing factor-encoded genes in bone marrow failure diseases, such as myelodysplastic syndromes (MDS) and related disorders. In particular, mutations in the splicing factor SRSF2 were significantly associated with mutations of RUNX1, a transcription factor with an established role in various blood cell disorders. These findings suggest a critical role of thes factors in blood cell pathology, likely through their synergistic effects in regulated gene expression, and potentiate the development of new therapeutics against specific types of bone marrow failure disorders. The goal of this proposal is to establish the causal role of SRSF2 mutations and their genetic interactions with RUNX1 in bone marrow disorders. Our labs have been systematically pursuing the biological function and regulatory mechanisms of RUNX1 (Zhang lab) and SRSF2 (Fu lab) for many years. Recently, our research has led to novel insights into the mechanism of these genes in regulated gene expression. We have an established collaborative record, and our combined expertise is ideally suited to pursue the disease mechanism and develop novel therapeutic strategies through a concerted effort. Therefore, we propose to join forces to attack the problem under the following specific aims: 1) Establish causal mutations of SRSF2 and RUNX1 in MDS. We hypothesize that the mutations synergistically promote abnormal blood cell proliferation and development. 2) Understand the impact of the Proline 95 mutations on the functional properties of SRSF2. We hypothesize that MDS-associated mutations in SRSF2 may have altered the function of SRSF2 to affect specific splicing and/or transcription events that are critical for the development of blood cells. 3) Defin critical molecular pathways underlying the disease phenotype. We hypothesize that mutations in these genes cause specific changes in regulated gene expression to favor disease development. We propose to define the altered molecular pathways using both cells isolated from animal models and human patient samples. In sum, we design the research through testing key hypotheses by using the latest genetic and genomic approaches. This proposal takes full advantage of our many years of effort and experience in basic and translational research. The studies are expected to provide valuable insights into the pathology of SRSF2 and RUNX1 mutation related bone marrow failure diseases, which will eventually benefit patients by facilitating the development of pathway directed chemical screening strategies.

描述（由申请人提供）：最近的大规模测序工作揭示了骨髓衰竭疾病（如骨髓增生异常综合征（MDS）和相关疾病）中剪接因子编码基因的普遍突变。特别是，剪接因子SRSF 2的突变与RUNX 1的突变显著相关，RUNX 1是一种在各种血细胞疾病中具有既定作用的转录因子。这些发现表明这些因子在血细胞病理学中的关键作用，可能是通过它们在调节基因表达中的协同作用，并加强了针对特定类型骨髓衰竭疾病的新疗法的开发。该提案的目标是确定SRSF 2突变及其与RUNX 1的遗传相互作用在骨髓疾病中的因果作用。本实验室多年来一直在系统地研究RUNX 1（Zhang实验室）和SRSF 2（Fu实验室）的生物学功能和调控机制。最近，我们的研究对这些基因调节基因表达的机制有了新的见解。我们有一个既定的合作记录，我们的综合专业知识非常适合通过共同努力来探索疾病机制和开发新的治疗策略。因此，我们建议在以下具体目标下联合起来解决这个问题：1）在MDS中建立SRSF 2和RUNX 1的因果突变。我们假设突变协同促进异常血细胞增殖和发育。2)了解脯氨酸95突变对SRSF 2功能特性的影响。我们假设SRSF 2中MDS相关突变可能改变了SRSF 2的功能，从而影响对血细胞发育至关重要的特定剪接和/或转录事件。3)定义疾病表型的关键分子通路。我们假设这些基因的突变导致调控基因表达的特定变化，以促进疾病的发展。我们建议使用从动物模型和人类患者样本中分离的细胞来定义改变的分子途径。总之，我们通过使用最新的遗传学和基因组学方法测试关键假设来设计研究。该提案充分利用了我们在基础和转化研究方面的多年努力和经验。这些研究有望为SRSF 2和RUNX 1突变相关的骨髓衰竭疾病的病理学提供有价值的见解，最终将通过促进途径导向的化学筛选策略的发展而使患者受益。