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Research Overview

Dr. Gazda’s laboratory studies molecular causes and pathothysiology of DBA and developed mouse models of DBA with the goal of finding the better treatment than what is currently available for DBA patients.

Her laboratory closely collaborates with several researchers from Boston Children’s Hospital and international institutions.

Laboratory Projects:

  1. Diamond-Blackfan anemia gene discovery:Using high-throughput genetic screening, array comparative genomic hybridization and whole exome sequencing, we identified mutations in ten (nine ribosomal protein genes and GATA1) out of eighteen DBA genes. However, ~35% of DBA patients still do not have a molecular diagnosis. We plan to perform whole genome sequencing on samples from whole exome sequencing unsolved DBA families to identify the remaining genes whose mutations are responsible for DBA.

  2. Drug discovery for Diamond-Blackfan anemia:Sankaran’s laboratory and our group demonstrated that decreased GATA1 translation underlies Diamond-Blackfan anemia in ribosomal protein gene mutated patients. We have also generated RPL5 deficient mice using transgenic RNAi interference (shRNA Rpl5 ). The doxycycline treated shRNA Rpl5 mice exhibit anemia mimicking DBA and have decreased GATA 1 level in erythroid bone marrow cells. We want to search for compounds that can increase GATA1 expression in bone marrow erythroid cells from these mice. We hope that positive hits applied in vivo will ameliorate anemia in shRNA Rpl5 mice and subsequently in patients with DBA.

  3. Mechanism of sarcoma in DBA:Recent studies conducted by the DBA Registry of North America revealed that the relative risk of cancer in DBA was increased 5.4 fold compared to the general population. Our study on mouse models of DBA revealed increased incidence of soft tissue sarcoma and osteosarcoma compared to wild type mice. We study the mechanism of sarcoma in Rps24+/- and Rpl5 +/- mice to shed light on mechanism of sarcoma in DBA patients.

Research Background

Dr. Gazda obtained her M.D. and Ph.D. degrees from the Medical University of Warsaw, Poland. Following Pediatric residency in Poland, she moved to the Unites States for a postdoctoral fellowship at Dana-Farber Cancer Institute where she studied genetic causes of Diamond-Blackfan anemia (DBA), a congenital hypoplastic anemia and a broad developmental disease that usually presents early in infancy and is associated with birth defects and increased likelihood of developing malignancy. She then moved to Boston Children’s Hospital where she continued her studies on molecular causes and pathogenesis of DBA. Her work on genetic causes of DBA reinforced the notion that DBA is a ribosomal disease. She established her own laboratory at Boston Children’s Hospital in 2010 and she is presently an Assistant Professor at Harvard University.

Selected Publications

  1. Ludwig LS, Gazda HT, Eng JC, Eichhorn SW, Thiru P, Ghazvinian R, George TI, Gotlib JR, Beggs AH, Sieff CA, Lodish HF, Lander ES, Sankaran VG. Altered translation of GATA1 in Diamond-Blackfan anemia. Nat Med. 2014; 20:748-53.
  2. Sankaran VG, Ghazvinian R, Do R, Thiru P, Vergilio J-A, Beggs AH, Sieff CA, Orkin SH, Nathan DG, Lander ES, Gazda HT. Exome Sequencing Identifies GATA1 Mutations Resulting in Diamond-Blackfan Anemia. J Clin Invest. 2012; 122:2439-43.
  3. Doherty L, Sheen MR, Vlachos A, Choesmel V, O'Donohue MF, Clinton C, Schneider HE, Sieff CA, Newburger PE, Ball SE, Niewiadomska E, Matysiak M, Glader B, Arceci RJ, Farrar JE, Atsidaftos E, Lipton JM, Gleizes PE, Gazda HT. Ribosomal protein genes RPS10 and RPS26 are commonly mutated in Diamond-Blackfan anemia. Am J Hum Genet. 2010;86:222-8.