Signaling Pathways in MDS

MDS 中的信号通路

• 批准号: 9114296
• 负责人: Shuo Lin
• 金额: $ 11.32万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-10 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9114296
• 关键词: Acute Myelocytic Leukemia; Anemia; Anti-Inflammatory Agents; Anti-inflammatory; Biological; CD34 gene; Cell Line; Cells; Chronic; Defect; Development; Diamond-Blackfan anemia; Disease; Dysmyelopoietic Syndromes; Embryo; Erythrocytes; Erythroid; Erythropoiesis; Event; FDA approved; Genes; Goals; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Human; Immune; In Vitro; Inflammatory; Lead; Libraries; Modeling; Molecular; Normal Cell; Pancytopenia; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Protein Deficiency; Protein Subunits; Public Health; Quality of life; Regulation; Relapse; Research; Ribosomal Proteins; Risk; Role; Signal Pathway; Signal Transduction; Stem cells; Testing; Transfusion; Work; Zebrafish; bone marrow failure syndrome; chemokine; chemotherapy; chromosome 5q loss; cytokine; improved; in vivo; lenalidomide; mutant; novel; novel strategies; public health relevance; stem; targeted treatment; transcriptome sequencing

 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.

 描述（由适用提供）：核糖体蛋白亚基14（RPS14）缺乏在DEL（5Q）骨髓增生综合征（MDS）的发病机理中的作用尚不清楚。尽管治疗了Lenalidomide的MDS患者，但50％的患者仍未反应，并且这些患者患急性骨髓性白血病（AML）的风险增加。贫血患者可能需要慢性红细胞输血，导致生活质量受损。 RPS14的单倍不足是DEL（5Q）MDS中的贫血表型的原因。因此，了解与DEL（5Q）MDS中RPS14缺乏相关的红细胞生成缺陷的基础机制，并开发出新的治疗该疾病的疗法。为了研究核糖体蛋白质不足和骨髓衰竭下游的分子途径，我们用RPS19缺乏的人CD34+造血词干和祖细胞进行了RNA-SEQ，以模拟钻石黑芬贫血，并发现在RPS19和RPS14-DEFECITIC Qualtitic Qualtitic Qualtitic progitor progitor symatietic progitor symatopopoemopopopoematietic progitor progitor symatopopoematietic progitor progitietic progitor progitor symatopopoe疗法中都受到了异常调控。其中几个基因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定义DEL（5Q）MDS中RPS14缺乏的发病机理的信号传导途径，并测试免疫调节和抗炎药，以使用人和斑马鱼模型来营救贫血。我们提出了三个具体目标。在AIM 1中，我们将表征信号通路在RPS14缺乏的人MDS模型中调节红细胞生成。在AIM 2中，我们将表征信号通路在RPS14缺乏斑马鱼中调节红细胞生成。在AIM 3中，我们将鉴定并测试已知化合物，以开发潜在的新型疗法，以治疗DEL（5Q）MDS中的红细胞缺损。我们的研究将提高我们对MD的理解，并导致潜在的治疗DEL（5Q）MDS的新方法。