Identification of Genetic Co-Modifiers in Shwachman-Diamond Syndrome
Abstract
The goal of this proposal was to develop a powerful model for Shwachman-Diamond Syndrome that could ultimately be used to identify genetic co-factors for the development of myelodysplastic syndrome/acute myeloid leukemia (MDS/AML). We have hypothesized that SBDS damages hematopoietic stem cell and/or stroma, and that through the power of zebrafish modeling, we can identify the cellular and genetic lesions that promote MDS/AML. This model will allow us to 1) to carry out large scale screening for genetic co-modifiers that promote leukemogenesis followed by their validation, and 2) to carry out drug screening for compounds to modify SBDS-positive cells. We have generated transgenic zebrafish line harboring SBDS gene promoter fused with fluorescent protein Cherry and demonstrated that the gene is broadly expressed during embryonic development in various tissues, including hematopoietic and digestive systems while the expression is sparsely distributed (stem cells?) in juvenile and adult animals. We have also initiated a study on generation of ZFN-induced mutations in SBDS gene. Currently, we have been able demonstrate that sbds-specific ZFN does induced mutation in the targeted gene and that this mutation is lethal in early embryos which, however, can be rescued by SBDS-specific mRNA. This study creates a foundation for establishment of a unique animal model of SBDS.
Document Details
- Document Type
- Technical Report
- Publication Date
- Mar 01, 2013
- Accession Number
- ADA592341
Entities
People
- Sergei Revskoy
Organizations
- Northwestern University