Craig M Crews Ph.D.
Lewis B. Cullman Professor of Molecular, Cellular, and Developmental Biology and Professor of Chemistry and of Pharmacology; Executive Director, Yale Molecular Discovery Center
Limb regeneration; wound epidermis; blastema; natural product mode of action studies; angiogenesis; Wnt signaling; protein turnover; protein kinase regulation
Current ProjectsSalamander Limb Regeneration: We studying the role of regeneration-specific genes in inducing cellular dedifferentiation.
Inducing Protein Turnover: We are developing new methodologies to use cell-permeable small molecules as inducers of targeted protein degradation.
We use a combination of biochemistry, molecular biology, and bio-organic chemistry to explore different aspects of developmental and cell biology. Different projects include 1) the exploration of salamander limb regeneration with the goal of applying this knowledge to the possibility of mammalian regeneration, and 2) the exploration of how biologically active compounds from nature work in order to identify new probes for cell biology as well as identify novel drug targets.
Extensive Research Description
Among tetrapods, urodele amphibians such as Mexican salamanders (aka axolotls) have the unique ability to regenerate missing lens, tails, jaws, and tails. This epimorphic phenomenon begins with the closure of the wound via migration of the existing surrounding epidermis, which over the course of several days becomes an unique structure known as the Regenerative Epidermis (RE). The RE is required for regeneration since its removal prevents limb regrowth; however, it is unclear if the RE plays a 'permissive' or an 'inductive' role in the generation of the undifferentiated cell mass (aka blastema) that accumulates under the RE. We have recently identified 124 genes that are expressed 1.5x more highly in the RE relative to non-regenerating, wound healing epidermis. We are currently exploring several of these secreted and membrane-bound proteins to determine if they play an inductive role in cellular dedifferentiation (i.e., blastema formation). If so, this induction of adult dedifferentiated cells could be considered a natural analogy to the generation of iPS cells in cell culture.In addition to our interest in regenerative medicine, we are also developing novel reagents, which will allow us to explore new areas in cell biology. This 'chemical genetic' approach uses biologically active natural products and de novo designed small molecules to identify critical components in intracellular processes. In the past few years, our efforts have focused on anti-angiogenic, antitumor and anti-inflammatory natural products. More recently, we have explored the use of small molecules to control intracellular protein levels, either by inhibiting their degradation or by inducing their proteolysis via the 26S proteasome. A goal of this research is to develop novel methodologies that would allow for small molecule control of the 'undruggable proteome'.