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）：钻石黑扇贫血症 (DBA) 是一种异质性疾病，患者表现为纯红细胞再生障碍、先天性异常和癌症风险增加。核糖体蛋白亚基 (RPS) 19 和 11 的突变已有描述。我们建议表征斑马鱼、小鼠和人类造血模型系统中 RPS19 和 RPL11 缺陷导致的分子途径，以了解 DBA 的发病机制。根据我们的初步数据，我们将研究 RPS19 和 RPL11 水平的降低如何改变 p53 蛋白质网络以及通过 Mdm2 和其他调节因子对 p53 的调节。我们假设 p53 在发育过程中受到差异性调节。我们的结果和其他人发表的工作表明，p53 主要在早期发育过程中进行转录调节，但在更成熟或成体细胞中进行翻译后调节。在具体目标 1 中，我们将开发具有 RPS19 或 RPL11 缺陷的不同斑马鱼模型，以表征 p53 相关蛋白在 DBA 和恶性转化中的作用。在具体目标 2 中，我们将在体外和体内研究 RPS19 和 RPL11 缺陷的人类和小鼠原代造血细胞中的 p53 信号通路。抑制素作为 RPS19 不足的下游靶点的作用也将得到研究。在具体目标 3 中，我们将评估调节 RPS19 和 RPL11 敲低造血细胞中 p53 活性的已知化合物，作为治疗 DBA 的可能治疗方法。我们还建议使用斑马鱼胚胎来鉴定 FDA 批准的挽救 RPL11 表型的药物。通过这种方式，信号通路将与斑马鱼的发育异常和造血缺陷联系起来。我们的研究将为 DBA 的分子发病机制提供新的见解，并为 DBA 患者的治疗带来新的途径。公共卫生相关性：该项目与公共卫生相关，因为它的重点是确定治疗 DBA 的新途径和开发新方法。因此，这项工作的结果将改善 DBA 患者的生活质量。