Signaling Pathways in MDS

 描述(由申请人提供)：核糖体蛋白14亚单位(RPS14)缺乏在del(5q)骨髓增生异常综合征(MDS)发病机制中的作用尚不清楚。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。贫血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del(5q)MDS中与RPS14缺乏相关的红细胞生成缺陷的潜在机制并开发新的治疗方法是至关重要的。为了研究核糖体蛋白缺乏和骨髓衰竭的下游分子通路，我们对RPS19缺陷的人CD34+造血干细胞和祖细胞进行了RNA-SEQ，建立了Diamond Blackfan贫血模型，发现与正常细胞相比，RPS19和RPS14缺陷的造血祖细胞中都存在异常调控的基因。这些基因中有几个是调节炎症途径的细胞因子和趋化因子。这项研究的目的是进一步明确在del(5q)MDS中RPS14缺乏的发病机制，并使用人类和斑马鱼模型测试免疫调节和抗炎药物来拯救贫血。我们提出了三个具体目标。在目标1中，我们将描述RPS14缺陷的人类MDS模型中调节红细胞生成的信号通路。在目标2中，我们将描述RPS14缺陷斑马鱼中调控红细胞生成的信号通路。在目标3中，我们将鉴定和测试已知的化合物，以开发潜在的新疗法来治疗del(5q)MDS的红系缺陷。我们的研究将增加我们对MDS的理解，并导致潜在的治疗Del(5q)MDS的新方法。

 DESCRIPTION (provided by applicant): 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.