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

项目概要/摘要 最近的大规模测序工作已经揭示了剪接因子编码的 基因在骨髓衰竭疾病，如骨髓增生异常综合征（MDS）和相关 紊乱特别是，剪接因子SRSF 2的突变与 RUNX 1是一种转录因子，在各种血细胞疾病中发挥作用。 这些发现表明这些因素在血细胞病理学中的关键作用，可能是通过它们的 在调节基因表达中的协同作用，并加强新疗法的开发 针对特定类型的骨髓衰竭疾病。该提案的目标是建立 骨髓疾病中SRSF 2突变及其与RUNX 1的遗传相互作用的因果作用。 我们的实验室一直在系统地追求的生物功能和调节机制， RUNX 1（Zhang实验室）和SRSF 2（Fu实验室）多年。最近，我们的研究发现了一种新的 这些基因在调控基因表达的机制的见解。我们有一个既定 合作记录，我们的综合专业知识非常适合研究疾病机制 并通过共同努力开发新的治疗策略。因此，我们建议加入 在以下特定目标下攻击该问题的力量：1）建立SRSF 2的因果突变 MDS中的RUNX 1。我们假设突变协同促进异常血细胞 扩散和发展。2)了解脯氨酸95突变对功能性 SRSF 2的特性。我们假设SRSF 2中MDS相关的突变可能改变了 SRSF 2的功能，以影响特定的剪接和/或转录事件，这是关键的 血细胞的发育。3)定义疾病表型的关键分子途径。 我们假设这些基因的突变引起受调控基因表达的特定变化， 有利于疾病的发展。我们建议使用这两种细胞来定义改变的分子途径 分离自动物模型和人类患者样品。总而言之，我们通过以下方式设计研究： 通过使用最新的遗传学和基因组学方法测试关键假设。该提案充分考虑了 我们在基础和转化研究方面的多年努力和经验的优势。研究 预计将为SRSF 2和RUNX 1突变相关的病理学提供有价值的见解 骨髓衰竭疾病，这将最终有利于患者的发展， 途径导向的化学筛选策略。

Project Summary/Abstract 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 these 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) Define 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.