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James Chen received his A.B. and Ph.D. degrees in Chemistry and Chemical Biology from Harvard, and he completed his postdoctoral studies at the Department of Molecular Biology and Genetics at Johns Hopkins. He joined the Stanford faculty in 2003, and his research interests span organic chemistry, chemical biology, developmental biology, and cancer biology.The Chen lab investigates the molecular mechanisms that underlie tissue formation and tumorigenesis, guided by chemical principles and enabled by chemical technologies. For example, the Chen group has developed small-molecule inhibitors of Hedgehog signaling, a biochemical pathway that is required for multiple aspects of embryonic development and contributes to human cancer. They discovered the first specific inhibitors of cytoplasmic dyneins, microtubule motors that regulate a signaling organelle called the primary cilium, and first-in-classes inhibitors of aldehyde dehydrogenase 1B1, a mitochondrial that promotes colorectal and pancreatic cancer. In addition, members of the lab have synthesized photoactivatable antisense oligonucleotides that allow gene expression to be suppressed with spatiotemporal precision. By applying these tools in zebrafish embryos, they have elucidated the transcriptional programs that regulate formation of the notochord, somites, and other mesodermal tissues. The Chen group also collaborated with the Harbury lab to devise new methods for time-resolved lanthanide microscopy. This approach takes advantage of the long-lived photoluminescence of lanthanide chelates, and it enables ultrasensitive, autofluorescence-free imaging of whole organisms.Current research interests in the lab include small-molecule modulators of cancer stem cell metabolism, optogenetic tools for controlling cell signaling, the biochemical and cellular processes that drive spermiogenesis, and the development of non-hormonal male contraceptives.
The Chen laboratory integrates chemistry and developmental biology to investigate the molecular mechanisms that control tissue formation, regeneration, and malignancy. Our research group is currently focused on three major areas: (1) small-molecule and genetic regulators of Hedgehog signaling; (2) chemical tools for studying tissue patterning at the molecular and systems levels; and (3) animal models of development and cancer.Our interest in the Hedgehog pathway arises from its critical role in the embryonic patterning of multiple tissues. Aberrant Hedgehog pathway activation in children and adults is also linked to several cancers, including those of the skin, brain, and blood. Since the cellular events that transduce the Hedgehog signal from the cell surface to the nucleus are not well understood, we have pursued genetic and small-molecule screens for new Hedgehog pathway modulators with novel modes of action. These studies will provide insights into the basic mechanisms of Hedgehog signal transduction, as well as targets and chemical leads for new therapies.Our efforts to develop new tools for in vivo biology have focused on the zebrafish models, exploiting the rapid ex utero development, amenability to both chemical and genetic perturbations, and optical transparency of this vertebrate. For example, we have developed caged antisense oligonucleotides and photoactivatable proteins that afford precise spatiotemporal control of developmental signaling pathways. We have also devised new methods for time-resolved lanthanide microscopy, enabling ultrasensitive, autofluorescence-free imaging. In conjunction with genetic approaches, these chemical technologies can open new windows into the molecular mechanisms that control vertebrate development and physiology.Most recently, we have initiated studies of spermatogenesis using rodent models. Our investigations explore how the testis-specific kinase HIPK4 promotes male fertility, and our findings indicate that this signaling protein is required for spermatid elongation. Our goals are to elucidate how this kinase and its substrates regulate the cytoskeletal forces that remodel the spermatid nucleus and to develop HIPK4-specific inhibitors. In principle, such antagonists could provide safe and reversible male contraception.