Research Description

Our group was one of the first to develop a systematic structure to explain why genotype did not predict phenotype for human genetic diseases, and why the phenotypes of even “simple” Mendelian disorders are complex traits. We are now using cultured cells and model organisms to explore this complexity, focusing on the following genetic diseases. Glycerol kinase deficiency (GKD) can be caused by a contiguous gene deletion syndrome (complex GKD of cGKD) involving Xp21 or point mutations affecting only the GK gene. We are developing methods and algorithms to identify small gene deletions using representational oligonucleotide microarray analysis (ROMA) for Xp21 and other genomic deletions as well as genome-wide single nucleotide polymorphism (SNP) analyses to identify modifier loci. To investigate the pathogenesis of isolated GKD we are examining gene expression microarrays using tissues from Gyk knockout (KO) mice and systems biology algorithms to reduce the high dimensionality microarray data to low dimensionality output. These results are identifying other pathways in which the GK protein is involved, including apoptosis. Investigations of the gene immediately telomeric to GK, known as DAX1or NR0B1, are being performed in zebrafish. In humans, loss of DAX1 function leads to abnormal development of the adrenal glands and death. We have demonstrated DAX1 expression in the interrenal gland (adrenal equivalent) in zebrafish. We are using methods developed in Dr. James Dunn’s laboratory (also in Bioengineering) in mice to attempt to identify adrenal stem cells in zebrafish, and we are developing micro-devices to separate these stem cells from the larger bulk of cells – essentially fluorescence activated cell sorting (FACS) on a chip. Dax1 is the earliest expressed marker in zebrafish tooth development and we are investigating its role in initiation of the primary tooth and in enamelogenesis. Our investigations in adrenal and tooth development are proposed to have eventual applications in regenerative medicine. We are collaborating on a variety of device-development projects to facilitate our research and that of others.