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.
. 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.
