CAREER: Small Molecule-Mediated Axonal Regeneration

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With this CAREER Award from the Chemistry of Life Processes Program Professor Dionicio Siegel of the University of Texas at Austin will examine new ways to promote axonal regeneration through the use of small molecules. With a set of natural products and analogs that the PI's laboratory has synthesized and demonstrated to possess growth promoting and regenerative activities, both in vitro and in vivo, the molecular events leading to regeneration will be investigated. Due to the challenges of determining the modes of action of small molecules the researchers will use a variety of different methods for target identification including covalent adduct formation (photo-affinity and electrophilic baits) and drug affinity responsive target stability.  These studies will be conducted in combination with APEX mass spectroscopy-based quantitative proteomic analyses. The determination of the mode(s) of action will provide insight into how to control axonal growth and development using small molecules. A second project focused on axonal regeneration will develop laboratory preparations of the natural products xanthofulvin and vinaxanthone.  Both compounds strongly inhibit the inhibitor of axonal regeneration, semaphorin3A.  Xanthofulvin has been studied in vivo in adult rats and leads to remarkable regeneration following complete spinal cord transection. The lack of a laboratory preparation, however, has limited studies to advance the understanding of xanthofulvin's biological effects. The group will test a proposed non-enzymatic dimerization sequence that generates the compounds during fermentation or isolation. The completion of the syntheses will provide a platform for future studies focused on optimizing the biological performance of the compounds.Professor Siegel's freshman research class "Bioprospecting: Isolation of Biologically Active Natural Products from Endophytes" exposes students to a unique combination of botany, ethnobotany, mycology, pharmacology, and organic chemistry providing broad exposure to multiple scientific areas.  In addition, the research is in line with the research group's focus in regeneration and the extracts prepared through this class are screened in the Siegel lab's C. elegans-based neuronal outgrowth assays.  The class utilizes the unique capabilities of the research group, existing collaborations, and the nature conservatory facilities at the Lady Bird Johnson Wildflower Center. Designed by Dr. Siegel to encourage pursuit of careers in the chemical sciences "Texas Shamans" is a program that offers Title I high school students the rare opportunity to participate in genuine research. Seeking to include those currently underrepresented in the sciences, Texas Shamans is aimed specifically at students from low-income families, large concentrations of which are the criterion for Title I designation.  The program studying natural products in native Texas plants has been successfully implemented in ten pilot workshops over the past three years and is being expanded to encompass more Austin area schools and provide a conduit for the placement of students into the research labs of University of Texas at Austin.