Current Research and Scholarly Interests
The Chen laboratory integrates synthetic chemistry and developmental biology to interrogate the molecular mechanisms that control embryonic patterning, tissue regeneration, and oncogenesis. Our research group is currently focused on three major areas: the identification of small-molecule and genetic regulators of Hedgehog signaling, the development of chemical technologies for perturbing and observing the molecular programs of embryonic patterning and tumorigenesis, and the study of tissue regeneration using zebrafish as a model organism.
Our interest in the Hedgehog pathway arises from its critical role in the patterning of multiple tissues such as the neural tube, craniofacial structures, limbs, and somites. Aberrant Hedgehog pathway activation in children and adults is also linked to several cancers, including those of the skin, brain, and gut. Since the cellular events that transduce the Hedgehog signal from the cell surface to the nucleus are not well understood, we are pursuing genetic and small-molecule screens for new Hedgehog pathway modulators with novel modes of action. These studies will not only provide insights into the basic mechanisms of Hedgehog signal transduction but also provide chemical leads for the development of next-generation chemotherapies and reveal new druggable targets within this tumor-promoting pathway.
Our laboratory is also investigating how Hedgehog signaling and other developmental pathways regulate tissue formation and regeneration in vertebrates. We use the zebrafish as a model organism for these studies, exploiting its rapid ex utero development, amenability to both chemical and genetic perturbations, and optical transparency during embryonic and larval stages. As part of these efforts, we have developed new strategies for activating and silencing gene expression in zebrafish embryos with unprecedented spatial and temporal precision. These methods utilize chemical probes developed by our research group, including caged reagents that allow light-or enzyme- controlled gene silencing in whole organisms. We have also developed new methods for time-resolved lanthande microscopy, enabling ultrasensitive, autofluorescence-free imaging of biological molecules. In conjunction with genetic approaches, these chemical technologies will help us elucidate the genetic programs that control vertebrate development and physiology.
Understanding the molecular mechanisms that underlie tissue regeneration is an emerging interest in our laboratory. The zebrafish is an ideal system for studying these processes, since it has the unique ability to regenerate its heart, retina, spinal cord, fins, and other body parts. We have investigated the molecular and cellular events associated with larval tail regeneration, and we are now developing optogenetic tools for studying tissue injury and repair.