Molecular Pathogenesis of Diamond Blackfan Anemia

钻石黑扇贫血症的分子发病机制

基本信息

批准号：
8011700
负责人：
Shuo Lin
金额：
$ 38.5万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-01-07 至 2011-11-07
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8011700
关键词：
Adult Apoptosis Automobile Driving Biological Models Blood Cell model Cells Congenital Abnormality Data Defect Development Diamond-Blackfan anemia Disease Embryo Erythroid FDA approved Family Family member Functional disorder Genetic Models Hematopoiesis Hematopoietic Hematopoietic Neoplasms Human In Vitro Inborn Genetic Diseases Incidence Lead Libraries Link Malignant - descriptor Malignant Neoplasms Mammalian Cell Modeling Molecular Mus Mutation Neonatal Pancytopenia Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Phenotype Post-Translational Regulation Protein Deficiency Protein Subunits Proteins Public Health Publishing Pure Red-Cell Aplasia Quality of life RPS19 gene Regulation Ribosomal Proteins Role Signal Pathway Signal Transduction Stem cells Syndrome Testing Therapeutic Up-Regulation Work Zebrafish base cancer risk clinical phenotype exhaustion fetal improved in vivo inhibin insight novel novel strategies novel therapeutic intervention p53 Signaling Pathway pressure progenitor public health relevance ribosomal protein S19

项目摘要

DESCRIPTION (provided by applicant): Diamond Blackfan Anemia (DBA) is a heterogeneous disease in which patients present with pure red cell aplasia, congenital abnormalities, and an increased risk of cancer. Mutations in ribosomal protein subunits (RPS) 19 and 11 have been described. We propose to characterize the molecular pathways resulting from deficiencies of RPS19 and RPL11 in the zebrafish and in mouse and human hematopoietic model systems to understand the pathogenesis of DBA. Based on our preliminary data, we will study how decreased levels of RPS19 and RPL11 alter the p53 network of proteins and the regulation of p53 through Mdm2 and other regulators. We hypothesize that p53 is differentially regulated during development. Our results and published work by others suggest that p53 is primarily regulated transcriptionally during early development, but post-translationally in more mature or adult cells. In Specific Aim 1, we will develop different zebrafish models with RPS19 or RPL11 insufficiency to characterize the role of p53 related proteins in DBA and malignant transformation. In Specific Aim 2, we will study p53 signaling pathways in human and mouse primary hematopoietic cells with RPS19 and RPL11 deficiency in vitro and in vivo. The role of inhibin as a downstream target of RPS19 insufficiency will also be investigated. In Specific Aim 3, we will evaluate known compounds regulating p53 activity in RPS19 and RPL11 knockdown hematopoietic cells as possible therapeutic approaches to treat DBA. We also propose to use zebrafish embryos to identify FDA approved drugs that rescue the RPL11 phenotype. In this manner, the signaling pathways will be linked to developmental anomalies in zebrafish and defects in hematopoiesis. Our studies will provide novel insights into the molecular pathogenesis of DBA and lead to new avenues for treatment of DBA patients. PUBLIC HEALTH RELEVANCE: This project is relevant to public health because it focuses on identifying new pathways and development of new approaches to treat DBA. Therefore, results from this work will improve the quality of life of DBA patients.

描述（由申请人提供）：钻石黑芬贫血（DBA）是一种异质性疾病，患者患有纯红细胞附属性，先天性异常和癌症风险增加。核糖体蛋白亚基（RPS）19和11的突变已被描述。我们建议表征斑马鱼和小鼠和人造血模型系统中RPS19和RPL11缺乏引起的分子途径，以了解DBA的发病机理。根据我们的初步数据，我们将研究RPS19和RPL11水平降低如何改变蛋白质的p53网络以及通过MDM2和其他调节剂对p53的调节。我们假设p53在开发过程中受到差异调节。我们的结果和其他人发表的工作表明，p53在早期发育过程中主要受到转录的调节，但在更成熟或成年细胞的后翻译。在特定目标1中，我们将开发具有RPS19或RPL11不足的不同斑马鱼模型，以表征p53相关蛋白在DBA和恶性转化中的作用。在特定目标2中，我们将研究具有RPS19和RPL11缺乏体外和体内的人和小鼠原代造血细胞中的P53信号通路。还将研究抑制素作为RPS19功能不全的下游靶标的作用。在特定的目标3中，我们将评估已知的化合物调节RPS19和RPL11敲低造血细胞中p53活性作为治疗DBA的治疗方法。我们还建议使用斑马鱼胚胎来识别FDA批准的拯救RPL11表型的药物。以这种方式，信号通路将与斑马鱼中的发育异常和造血缺陷有关。我们的研究将为DBA的分子发病机理提供新的见解，并为治疗DBA患者提供新的途径。公共卫生相关性：该项目与公共卫生有关，因为它着重于确定新的途径和开发新方法来治疗DBA。因此，这项工作的结果将改善DBA患者的生活质量。