Ongoing Research Projects

1. Ribosomes in marrow failure and malignancy

Ribosomal abnormalities form a common molecular theme underlying several inherited marrow failure syndromes, including Diamond-Blackfan anemia, dyskeratosis congenita, and Shwachman-Diamond syndrome.  Acquired haploinsufficiency of ribosomal proteins has also been linked with the 5q-myelodysplastic syndrome in the general population.  It is unclear how ribosomes, long regarded as serving a cellular "housekeeping" function, contribute to marrow failure and malignancy.  Recent studies of ribosomal pathways have uncovered unexpected and as yet poorly defined functions for specific ribosomal proteins.  Data from our laboratory in human systems as well as data from yeast implicate SBDS in 60S ribosome biogenesis and joining of the 40S and 60S ribosomal subunits.  

Research topics:

• Molecular function of SBDS in ribosome biogenesis
• Function of ribosomes during hematopoiesis
• Role of SBDS and ribosomes in oncogenesis
• High-throughput screens for   ribosomal pathways affecting hematopoiesis

2.  Translational control of gene expression during hematopoiesis and development

Regulation of higher eukaryotic gene expression at the level of protein translation remains poorly characterized.   Recent studies demonstrate that differential mRNA translational control plays a critical role during development. We have developed human and mouse model systems to define the role of differential mRNA translation in hematopoiesis and leukemogenesis.  We have also developed assays to investigate the molecular mechanisms regulating differential mRNA translational activation.

Research topics:

• Translational control during hematopoiesis
• Translational consequences of ribosomal defects associated with marrow failure and leukemogenesis

3.  The role of the mitotic spindle in genomic instability

Our studies of SBDS revealed a role for the mitotic spindle in genomic instability. We are pursuing the molecular mechanisms whereby SBDS promotes spindle stabilization.  We are also pursuing the functional consequences of SBDS loss on mitosis in hematopoietic cells and in mouse models. Translational studies of spindle stabilizing agents are ongoing.

Research topics:

• molecular function of SBDS during mitosis
• mitotic spindle stabilization
• identification of SBDS mitotic binding partners
• mouse models to study SBDS in mitosis
• yeast genetic studies of SBDS in mitosis

Ongoing clinical studies include:

1. North American Shwachman-Diamond Syndrome Registry and Repository

The Fred Hutchinson Cancer Research Center serves as the primary site for this longitudinal study of Shwachman-Diamond syndrome.  Collaborating centers include the University of Toronto and the University of Cincinnati.  We are collecting longitudinal medical information and clinical tissue samples from patients with Shwachman-Diamond syndrome.  The goals of the Registry are to define the natural history of Shwachman-Diamond syndrome, to improve diagnosis and treatment, and to advance medical care through the elucidation of the molecular mechanisms underlying Shwachman-Diamond syndrome.

2. Incidence of Fanconi anemia in patients presenting with radial ray anomalies.

In collaboration with Dr. Brian Lebow from the Department of Surgery at Children's Hospital Boston, we are investigating the incidence of Fanconi anemia in patients presenting with radial ray anomalies.  Since the Fanconi anemia chromosomal breakage assay is laborious, time-consuming, and expensive, we are investigating a western blot assay (Shimamura et al, Blood 2002, 100: 4649-4654) as a screening test for this disorder.  We are also investigating clinical markers that might identify which patients would benefit from Fanconi anemia testing.