Signaling Pathways in MDS

项目总结/摘要 核糖体蛋白亚基14（RPS 14）缺陷在糖尿病中的作用 del（5 q）骨髓增生异常综合征（MDS）的发病机制尚未完全了解。 尽管用来那度胺治疗MDS患者，50%的患者将不响应 这些患者患急性髓细胞白血病（AML）的风险增加。患者 贫血患者可能需要长期输注红细胞，导致生活质量受损。 RPS 14单倍不足是del（5 q）MDS贫血表型的原因。 因此，了解这些缺陷的机制至关重要， 在del（5 q）MDS中与RPS 14缺陷相关的红细胞生成， 治疗这种疾病的方法。 研究核糖体蛋白不足的下游分子通路 和骨髓衰竭，我们用RPS 19缺陷型人CD 34+进行了RNA-seq。 造血干细胞和祖细胞模型钻石黑扇贫血，并发现 在RPS 19和RPS 14缺陷的造血细胞中异常调节的基因 与正常细胞相比。其中一些基因是细胞因子， 调节炎症通路的趋化因子。本研究的目标是进一步 定义有助于RPS 14缺乏症发病机制的信号通路， del（5 q）MDS和测试免疫调节和抗炎药物，以挽救 贫血使用人类和斑马鱼模型。我们提出三个具体目标。在 目的1，我们将表征调节RPS 14中红细胞生成的信号通路。 缺陷型人MDS模型。在目标2中，我们将描述信号通路 在RPS 14缺陷的斑马鱼中调节红细胞生成。在目标3中，我们将确定和测试 已知的化合物开发潜在的新疗法来治疗红细胞缺陷， del（5q）MDS。我们的研究将增加我们对MDS的了解，并可能导致 治疗del（5 q）MDS的新方法。

Project Summary/Abstract The role of Ribosomal Protein Subunit 14 (RPS14) deficiency in the pathogenesis of del(5q) Myelodysplastic Syndromes (MDS) is not well understood. Despite treatment of MDS patients with lenalidomide, 50% of patients will not respond and these patients have an increased risk of acute myeloid leukemia (AML). Patients with anemia may require chronic red cell transfusions resulting in impaired quality of life. Haploinsufficiency of RPS14 is responsible for the anemia phenotype in del(5q) MDS. Therefore, it is critical to understand the mechanisms underlying the defects in erythropoiesis associated with RPS14 deficiency in del(5q) MDS and develop new therapies to treat this disease. To study the molecular pathways downstream of ribosomal protein insufficiency and bone marrow failure, we performed RNA-seq with RPS19 deficient human CD34+ hematopoietic stem and progenitor cells to model Diamond Blackfan Anemia, and found genes that were aberrantly regulated in both RPS19 and RPS14-deficient hematopoietic progenitor cells compared to normal cells. Several of these genes were cytokines and chemokines that regulate inflammatory pathways. The goal of this research is to further define the signaling pathways that contribute to the pathogenesis of RPS14 deficiency in del(5q) MDS and test immune modulatory and anti-inflammatory drugs to rescue the anemia using both human and zebrafish models. We propose three specific aims. In Aim 1, we will characterize signaling pathways regulating erythropoiesis in RPS14- deficient human MDS models. In Aim 2, we will characterize signaling pathways regulating erythropoiesis in RPS14-deficient zebrafish. In Aim 3, we will identify and test known compounds to develop potentially novel therapies to treat erythroid defects in del(5q) MDS. Our studies will increase our understanding of MDS and lead to potentially new approaches to treat del(5q) MDS.