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揭示了剪接因子编码的普遍突变 骨髓衰竭疾病的基因，例如骨髓增生异常综合征（MDS）和相关疾病 失调。特别是，剪接因子 SRSF2 的突变与 RUNX1 是一种转录因子，在各种血细胞疾病中发挥着重要作用。 这些发现表明这些因素在血细胞病理学中发挥着关键作用，可能是通过它们的作用 调节基因表达的协同效应，并加强新疗法的开发 对抗特定类型的骨髓衰竭疾病。该提案的目标是建立 SRSF2 突变的因果作用及其与 RUNX1 的遗传相互作用在骨髓疾病中的作用。 我们的实验室一直在系统地研究其生物学功能和调控机制。 RUNX1（张实验室）和SRSF2（傅实验室）多年。最近，我们的研究产生了新颖的 深入了解这些基因在调控基因表达中的机制。我们有一个既定的 合作记录，我们综合的专业知识非常适合研究疾病机制 并通过共同努力制定新的治疗策略。因此，我们建议加入 力量在以下具体目标下解决这个问题：1）建立SRSF2的因果突变 和 MDS 中的 RUNX1。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突变对功能的影响 SRSF2 的特性。我们假设 SRSF2 中与 MDS 相关的突变可能改变了 SRSF2 的功能是影响特定剪接和/或转录事件，这些事件对于 血细胞的发育。 3) 定义疾病表型背后的关键分子途径。 我们假设这些基因的突变会导致受调控基因表达的特定变化 有利于疾病的发展。我们建议使用两种细胞来定义改变的分子途径 从动物模型和人类患者样本中分离出来。总之，我们通过以下方式设计研究 使用最新的遗传和基因组方法测试关键假设。该提案充分考虑 凭借我们在基础和转化研究方面多年的努力和经验。研究 有望为 SRSF2 和 RUNX1 突变相关的病理学提供有价值的见解 骨髓衰竭疾病，最终将通过促进疾病的发展使患者受益 途径定向化学筛选策略。

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.