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

描述(申请人提供)：最近的大规模测序工作发现，在骨髓衰竭疾病中，剪接因子编码的基因普遍存在突变，如骨髓增生异常综合征(MDS)和相关疾病。特别是，剪接因子SRSF2的突变与RUNX1的突变显著相关，RUNX1是一种转录因子，在各种血细胞疾病中具有既定的作用。这些发现表明，这些因素在血细胞病理学中发挥了关键作用，可能是通过它们在调节基因表达方面的协同作用，并促进了针对特定类型的骨髓衰竭疾病的新疗法的开发。这项建议的目的是确定SRSF2突变及其与RUNX1的遗传相互作用在骨髓疾病中的因果作用。多年来，我们的实验室一直在系统地研究RUNX1(Zhang Lab)和SRSF2(FU Lab)的生物学功能和调控机制。最近，我们的研究对这些基因调控基因表达的机制有了新的见解。我们有既定的合作记录，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，我们建议联合起来解决这一问题，具体目标如下：1)建立MDS中SRSF2和RUNX1的因果突变。我们假设这些突变协同促进了异常血细胞的增殖和发育。2)了解Proline 95突变对SRSF2功能特性的影响。我们推测，SRSF2中与MDS相关的突变可能已经改变了SRSF2的功能，以影响对血细胞发育至关重要的特定剪接和/或转录事件。3)明确疾病表型的关键分子途径。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，从而有利于疾病的发展。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通路。总而言之，我们通过使用最新的遗传和基因组方法测试关键假设来设计这项研究。这项建议充分利用了我们在基础和翻译研究方面多年的努力和经验。这些研究有望为SRSF2和RUNX1突变相关的骨髓衰竭疾病的病理提供有价值的见解，最终将通过促进通路导向的化学筛选策略的发展而使患者受益。

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.