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Signaling Pathways in MDS

MDS 中的信号通路

基本信息

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
项目类别：
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

项目摘要

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.