One focus of our group is modeling human diseases in zebrafish. We then use the models to screen large chemical libraries for small molecule modulators of the disease-related phenotypes. The compounds we discover help us elucidate disease mechanisms and serve as starting points for developing new drug candidates.
Disease physiology is often complex and involves interactions between multiple organs and tissue types. Consequently, many diseases cannot be studied effectively using in vitro assays. The zebrafish is an excellent vertebrate model system to study many complex, non-cell autonomous diseases because the diseases can be studied in a native, whole-organism setting. In addition, compounds discovered in zebrafish screens have the advantage of having been selected for their ability to be active, efficacious, and well tolerated in animals.
Disease modeling and drug discovery projects past and present include:
Lysosomal Storage Disorders
Recent advancements in zebrafish gene editing technologies have enabled the modeling of a wide range of human diseases in this organism. Using CRISPR-Cas9, we are developing zebrafish models of lysosomal storage disorders for phenotypic characterization and high-throughput chemical screening.
In recent years, researchers in the lab have been studying mitochondrial biology, specifically as it relates to cellular metabolism. We are interested in identifying metabolites that can modulate metabolism and protect against cyanide-induced toxicity in zebrafish. The lab has also generated CRISPR-KO models of multiple forms of mitochondrial disease, including Leigh Syndrome, and plans to screen chemical libraries to identify small molecules that can protect against or restore physiological deficits associated with these diseases.
Acute myeloid leukemia (AML)
We generated a model of AML by expressing the human AML-causing oncogene AML1-ETO in zebrafish. These zebrafish accumulate granulocytic blast cells that resemble those found in humans with AML. In a robotic expression screen of thousands of small molecules, we discovered that nimesulide can reverse the oncogenic effects of AML1-ETO.
Heart failure and diabetes
We have created zebrafish models of diabetes and chemotherapy-induced heart failure and used the models to discover compounds that reverse the disease phenotypes. Ongoing studies include efficacy studies in mouse models, structure activity relationship (SAR) studies, and proteomic-based target identification studies.
Many neurodegenerative diseases involve selective apoptosis of subsets of neurons in the brain. We have developed transgenic zebrafish lines that model key aspects of these neurodegenerative diseases. We have also developed tools for tracking neuron loss in the brains of living zebrafish. Using these reagents, we are screening for small molecules that prevent neuronal cell death in the zebrafish models with the goal of identifying therapeutic leads for neurodegeneration.