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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL097561-03
Application #
8210812
Study Section
Special Emphasis Panel (ZRG1-VH-F (02))
Program Officer
Qasba, Pankaj
Project Start
2010-01-07
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
3
Fiscal Year
2012
Total Cost
$463,934
Indirect Cost
$73,217
Name
Stanford University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Danilova, Nadia; Wilkes, Mark; Bibikova, Elena et al. (2018) Innate immune system activation in zebrafish and cellular models of Diamond Blackfan Anemia. Sci Rep 8:5165
Youn, Minyoung; Wang, Nan; LaVasseur, Corinne et al. (2017) Loss of Forkhead box M1 promotes erythropoiesis through increased proliferation of erythroid progenitors. Haematologica 102:826-834
Rankin, Erinn B; Narla, Anupama; Park, Joseph K et al. (2015) Biology of the bone marrow microenvironment and myelodysplastic syndromes. Mol Genet Metab 116:24-8
Danilova, Nadia; Bibikova, Elena; Covey, Todd M et al. (2014) The role of the DNA damage response in zebrafish and cellular models of Diamond Blackfan anemia. Dis Model Mech 7:895-905
Bibikova, Elena; Youn, Min-Young; Danilova, Nadia et al. (2014) TNF-mediated inflammation represses GATA1 and activates p38 MAP kinase in RPS19-deficient hematopoietic progenitors. Blood 124:3791-8
Zhang, Y; Ear, J; Yang, Z et al. (2014) Defects of protein production in erythroid cells revealed in a zebrafish Diamond-Blackfan anemia model for mutation in RPS19. Cell Death Dis 5:e1352
Lu, Jing; Xin, Shengchang; Meng, Huan et al. (2013) A novel anti-tumor inhibitor identified by virtual screen with PLK1 structure and zebrafish assay. PLoS One 8:e53317
Wen, Andy Y; Landaw, Elliot M; Ochoa, Rachel et al. (2013) Increased abscess formation and defective chemokine regulation in CREB transgenic mice. PLoS One 8:e55866
Zhang, Ying; Morimoto, Kenji; Danilova, Nadia et al. (2012) Zebrafish models for dyskeratosis congenita reveal critical roles of p53 activation contributing to hematopoietic defects through RNA processing. PLoS One 7:e30188
Danilova, Nadia; Sakamoto, Kathleen M; Lin, Shuo (2011) Ribosomal protein L11 mutation in zebrafish leads to haematopoietic and metabolic defects. Br J Haematol 152:217-28

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