Small molecules are powerful tools for studying developmental biology because they provide timing and dosage control over developmental pathways that is difficult to achieve with genetic mutations. Unfortunately, only a handful of developmental pathways can currently be targeted with small molecules. We are discovering novel chemical modifiers of developmental pathways by exposing zebrafish embryos to libraries of structurally diverse small molecules and identifying those that induce specific developmental defects. Using screens of this type, we have discovered dozens of compounds that cause specific defects in hematopoesis, cardiac physiology, embryonic patterning, pigmentation, and morphogenesis of the heart, brain, ear, and eye and germ cell lineage.
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.
Neuroscience & Behavior
Behaviors are accessible readouts of the molecular pathways that control neuronal signaling. Our group develops tools and techniques for comprehensive and high-throughput behavioral phenotyping in the zebrafish. These tools have some potential to improve our understanding of the neuronal signlaing and may accelerate the pace of neuroactive drug discovery.
Zebrafish Reverse Genetics
Zebrafish have proven to be a powerful genetic tool over the years, primarily through forward genetic screens where fish are mutagenized (typically with chemical agent) and screened for obvious defects. We are now on the verge of the next exciting step in zebrafish genetics: reverse genetics! Using targeted DNA disruption, we are now making designer mutations in specific genes of interest. Here are some of the resent papers describing three different processes.