John Bixby, Ph.D.
Professor, Departments of Molecular and Cellular Pharmacology and Neurological Surgery
Vice Provost for Research
High Content Screening and Functional Genomics of the Nervous System
The mass of information available from the various genome projects, together with sophisticated image analysis and laboratory automation has created an opportunity to revolutionize the study of the nervous system. Our laboratory has developed methods to test hundreds of genes in hundreds of thousands of neurons each week and obtain quantitative information about cell morphology and gene expression. This “high throughput” capability allows us to tackle questions about development and regeneration using Systems Biology approaches. The biological problem we have focused on for the past six years has been to uncover genes that promote or prevent axon regeneration.
The Lemmon-Bixby lab has four ongoing projects related to axon regeneration. The first project springs from the fact that neurons in the peripheral nervous system are able to regenerate while neurons in the central nervous system (CNS) are not. By analyzing data from several molecular biological approaches we were able to identify 900 genes that are preferentially expressed in regenerating peripheral neurons; of particular interest is a sub-list of 40 transcription factors (TFs) that are likely to regulate expression of other genes. The top TF has been confirmed to enhance neurite growth when over-expressed in CNS neurons.
Our second project is based on the fact that young CNS neurons have a greater regenerative capacity than old CNS neurons (collaboration with Dr. Jeff Goldberg). We have used DNA microarray data to generate a list of 800 candidate genes. We have tested about 60% of the genes on our list, and have identified 4 TFs that have a robust effect on neurite growth: two enhance growth and two inhibit growth. Interestingly, the two TFs that enhance growth show decreased expression as development proceeds, and the two that inhibit axon growth show increased expression as the animal ages.
The third project is to test effects of overexpression of known signaling proteins (kinases and phosphatases). In this screen we have tested 724 genes, and have found a high percentage with significant effects on neurite growth (about 40 total). The data from this screen is allowing us to begin to build models of neuronal signaling networks underlying axon regeneration. We are also using cheminformatics (collaboration with Stephan Schuerer) to identify chemicals that alter the activity of the interesting signaling molecules.
The fourth project is to screen a chemical compound library to identify compounds that can overcome the regeneration-inhibitory effects of the injured CNS (collaboration with Prof. Young-Tae Chang, , National University of Singapore). We have identified four compounds that enhance axon growth of a variety of neurons in inhibitory environments. One of these has been found to enhance regeneration in an acute spinal cord injury model in vivo.
John Bixby, Ph.D.
- The Miami Project to Cure Paralysis
1095 NW 14th Terrace (R-48)
Miami, FL 33136
- (305) 243-8184
- (305) 243-3921
Society for Neurosciences
American Association for the Advancement of Science
American Society of Biochemistry & Molecular Biology