Signaling Pathways in MDS

项目摘要/摘要 核糖体蛋白14亚单位(RPS14)缺陷在糖尿病发病中的作用 Del(5q)骨髓增生异常综合征(MDS)的发病机制尚不清楚。 尽管用来那度胺治疗MDS患者，50%的患者将没有反应 这些患者患急性髓系白血病(AML)的风险增加。病人 患有贫血的患者可能需要长期输注红细胞，导致生活质量受损。 RPS14单倍体缺失是del(5q)MDS贫血表型的原因。 因此，了解这些缺陷背后的机制至关重要。 Del(5q)MDS与RPS14缺乏症相关的红细胞生成及其新进展 治疗这种疾病的疗法。 核糖体蛋白缺乏下游分子通路的研究 和骨髓衰竭，我们对RPS19缺陷的人CD34+进行了RNA-SEQ 造血干细胞和造血祖细胞建立钻石黑扇贫血模型 在RPS19和RPS14缺陷的造血系统中同时发生异常调控的基因 祖细胞与正常细胞相比。其中几个基因是细胞因子和 调节炎症途径的趋化因子。这项研究的目标是进一步 明确参与RPS14缺乏症发病机制的信号通路 Del(5q)MDS和测试免疫调节和抗炎药物以拯救 使用人类和斑马鱼模型进行贫血。我们提出了三个具体目标。在……里面 目的1，我们将描述RPS14中调节红细胞生成的信号通路。 缺乏人类MDS模型。在目标2中，我们将描述信号通路 调节RPS14缺陷斑马鱼的红细胞生成。在目标3中，我们将识别和测试 已知化合物开发潜在的治疗红系缺陷的新疗法 戴尔(5q)MDS。我们的研究将增加我们对MDS的理解，并潜在地导致 治疗del(5q)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.