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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：
8452179
负责人：
Shuo Lin
金额：
$ 44.17万
依托单位：
STANFORD UNIVERSITY
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 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8452179
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.

描述（由申请人提供）：Diamond Blackfan贫血（DBA）是一种异质性疾病，患者表现为纯红细胞发育不全、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。我们建议在斑马鱼、小鼠和人类造血模型系统中表征RPS19和RPL11缺陷导致的分子通路，以了解DBA的发病机制。基于我们的初步数据，我们将研究RPS19和RPL11水平的降低如何改变p53的蛋白网络以及通过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调节。我们的研究结果和其他人发表的研究表明，p53主要在早期发育过程中受到转录调控，但在更成熟或成年的细胞中受到翻译后调控。在Specific Aim 1中，我们将开发不同的RPS19或RPL11不足的斑马鱼模型，以表征p53相关蛋白在DBA和恶性转化中的作用。在Specific Aim 2中，我们将在体外和体内研究RPS19和RPL11缺乏的人和小鼠原代造血细胞中p53信号通路。抑制素作为RPS19不足的下游靶点的作用也将被研究。在Specific Aim 3中，我们将评估在RPS19和RPL11敲低造血细胞中调节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患者的治疗提供新的途径。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

p53 upregulation is a frequent response to deficiency of cell-essential genes.

DOI：
10.1371/journal.pone.0015938
发表时间：
2010-12-31
期刊：
PloS one
影响因子：
3.7
作者：
Danilova N;Kumagai A;Lin J
通讯作者：
Lin J

Defects of protein production in erythroid cells revealed in a zebrafish Diamond-Blackfan anemia model for mutation in RPS19.

DOI：
10.1038/cddis.2014.318
发表时间：
2014-07-24
期刊：
Cell death & disease
影响因子：
9
作者：
通讯作者：

Innate immune system activation in zebrafish and cellular models of Diamond Blackfan Anemia.

DOI：
10.1038/s41598-018-23561-6
发表时间：
2018-03-26
期刊：
Scientific reports
影响因子：
4.6
作者：
Danilova N;Wilkes M;Bibikova E;Youn MY;Sakamoto KM;Lin S
通讯作者：
Lin S

The role of the DNA damage response in zebrafish and cellular models of Diamond Blackfan anemia.

DOI：
10.1242/dmm.015495
发表时间：
2014-07
期刊：
Disease models & mechanisms
影响因子：
4.3
作者：
Danilova N;Bibikova E;Covey TM;Nathanson D;Dimitrova E;Konto Y;Lindgren A;Glader B;Radu CG;Sakamoto KM;Lin S
通讯作者：
Lin S

Loss of Forkhead box M1 promotes erythropoiesis through increased proliferation of erythroid progenitors.