This proposal outlines a 5-year program for the development of an academic research career in pediatric hematology/oncology. The principal investigator proposes to further his research experience and develop expertise in the mechanisms of inherited bone marrow failure syndromes through focused investigation of a novel pathway for the development of Diamond-Blackfan Anemia (DBA), a bone marrow failure syndrome that disrupts erythropoesis, leads to congenital abnormalities, and is a cancer-predisposition syndrome. This research program integrates extensive departmental and core facility resources at Johns Hopkins with the clinical resources of a national registry to provide a superb environment from which to develop an active and productive career in this field. Dr. Robert Arceci, a leader in pediatric hematology and oncology with expertise in abnormal myeloid development and molecular studies in leukemia, will sponsor and serve as chief mentor. Collaboration with the Diamond Blackfan Anemia Registry of North America (DEAR) will ensure access to critical patient samples and clinical data. An advisory committee of leaders in the fields of bone marrow failure, DBA and ribosome biogenesis will provide additional scientific and career mentoring. The research will focus on understanding the contribution of ribosomal protein abnormalities to the development of DBA through investigation of RPL35a, a large ribosomal subunit protein our laboratory identified as a novel cause of DBA.
The specific aims are to: 1) delineate the types and frequency of ribosomal protein mutations and their associated clinical characteristics by sequencing for mutations and comparative genomic hybridization analysis to identify deletions, 2) determine the cellular consequences of RPL35a abnormalities to hematopoesis using an inducible lentiviral siRNA model in hematopoietic cell lines and bone marrow, and 3) determine the molecular consequences of RPL35a abnormalities by analysis of ribosome assembly/mRNA recruitment and protein expression changes.

Public Health Relevance

. By carefully defining a new genetic cause of Diamond Blackfan anemia, these studies will improve the ability to diagnose and provide genetic counseling to at-risk families and may identify new targets for more effective treatments. This project will also have broader relevance in further defining the link between abnormalities of protein synthesis and bone marrow failure, birth defects, and cancer predisposition.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL092224-06
Application #
8451887
Study Section
Special Emphasis Panel (ZHL1-CSR-O (F1))
Program Officer
Werner, Ellen
Project Start
2009-04-26
Project End
2014-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
6
Fiscal Year
2013
Total Cost
$134,325
Indirect Cost
$9,950
Name
University of Arkansas for Medical Sciences
Department
Pediatrics
Type
Schools of Medicine
DUNS #
122452563
City
Little Rock
State
AR
Country
United States
Zip Code
72205
Farrar, Jason E; Quarello, Paola; Fisher, Ross et al. (2014) Exploiting pre-rRNA processing in Diamond Blackfan anemia gene discovery and diagnosis. Am J Hematol 89:985-91
Farrar, Jason E (2014) Diamond Blackfan anemia: a Cheshire cat of hematology. Pediatr Blood Cancer 61:1154-5
Vlachos, Adrianna; Farrar, Jason E; Atsidaftos, Eva et al. (2013) Diminutive somatic deletions in the 5q region lead to a phenotype atypical of classical 5q- syndrome. Blood 122:2487-90
Markello, Thomas C; Carlson-Donohoe, Hannah; Sincan, Murat et al. (2012) Sensitive quantification of mosaicism using high density SNP arrays and the cumulative distribution function. Mol Genet Metab 105:665-71
Farrar, Jason E; Dahl, Niklas (2011) Untangling the phenotypic heterogeneity of Diamond Blackfan anemia. Semin Hematol 48:124-35
Moore 4th, Joseph B; Farrar, Jason E; Arceci, Robert J et al. (2010) Distinct ribosome maturation defects in yeast models of Diamond-Blackfan anemia and Shwachman-Diamond syndrome. Haematologica 95:57-64