Abstract: Our lab studies signals that regulate the specification and maintenance of cell differentiation during early embryogenesis, tissue regeneration, and disease pathogenesis. We use the frog embryo and tissue culture cells as model systems, and study primarily the regulation and action of the TGFß superfamily of ligands. Specific areas of current interest include (full description of our interests can be found at whitman.med.harvard.edu):
1) TGFß specificity in pattern regulation during embryogenesis TGFß superfamily members regulate an extraordinary variety of biological processes, including the establishment of early embryonic body pattern, the formation and patterning of tissues and organ systems in later development, and the onset of pathological processes, including fibrosis, tumor metastasis, and angiogenesis, in the adult. One of our major goals has been to understand the basis for the tissue specific regulation of transcription that occurs in response to TGFß signaling. Several years ago, we identified a transcription factor in early embryos, FAST-1, that specifically directs TGFß signal transducers, the Smads, to early embryonic promoters. We arecurrently investigating how FAST-1 and other embryo-specific transcription factors mediate patterning by TGFßs.
2) Specificity of a small molecule natural product as an inhibitor of TGFß regulated wound healing, fibrosis, and tumor development. We are studying a natural product derivative that has been shown to act as a potent regulator of fibrosis and extracellular matrix deposition in vivo, and to inhibit TGFß signaling in vitro. This small molecule acts with ~1000 fold greater potency than current “rationally designed” inhibitors of TGFß signaling, and with unexplained specificity of action towards extracellular matrix deposition, making it a promising therapeutic for wound healing, tumor metastasis, and a wide range of fibrotic diseases. We have identified the first molecular targets for this compound, and are studying how these targets mediate the specific action of this compound.
3) Role of TGFßs in complex tissue regeneration. Xenopus tadpoles can fully regenerate their tails after amputation, re-forming organized muscle, nerves, and connective tissue. We have found that TGFß signaling is essential for this process, and are currently dissecting the multiple signaling steps that regulate regeneration of complex structures.
4) TGFß superfamily regulation of muscle size and development. Muscle size is negatively regulated by the TGFß ligand myostatin. The mechanisms controlling myostatin activity in vivo are poorly understood. We are currently studying novel mechanisms by which myostatin is locally regulated in the extracellular space, providing new insights into how muscle size is controlled in health and disease.