Neurological disease such as traumatic brain injury, stroke, epilepsy, and neurodegenerative disorders including Alzheimer's disease and Parkinson's disease place a great burden on our population. In order to withstand damage associated with these disorders, neurons utilize survival and repair mechanisms. Axon regeneration is one such mechanism that allows neurons to regrow an axon following destruction of the original axon. On a molecular level, axon regeneration requires the DLK signaling pathway that is conserved from worms to human. Dendrite regeneration is an additional survival and repair mechanism recently discovered in fly neurons that allows the neuron to respond to irreversible dendrite damage. Recent evidence also suggests that dendrite regeneration may be more widespread and robust that was initially thought. On a molecular level, there is no overlap between the required signaling pathways for axon and dendrite regeneration. This suggests neurons have an unidentified injury-response signaling pathway. Our preliminary studies suggest that dendrite regeneration correctly specifies regrowth of dendrites, and that these dendrites maintain several basic dendrite features. However, the extent to which dendrite regeneration restores dendrite maturity and functionality is still unknown. Furthermore, there are no known required genes for dendrite regeneration. In this project, will fill in gaps of knowledge with regards to the status of regenerated dendrites. Additionally, we will identify the first required genes for dendrite regeneration. This work will greatly enhance our understanding of this process, and facilitate future studies on dendrite regeneration. In order for dendrite regeneration to ultimately be successful, mature and functional dendrites must be the end product of dendrite regeneration. To investigate the maturity and functional status of regenerated dendrites, we will use defined assays in Drosophila to determine if regenerated dendrites prune and respond to nociceptive stimuli. Discovery of any potential shortcomings in dendrite regeneration will be important, as these may become therapeutic targets for neurological disease in the future. To identify genes required for dendrite regeneration, we will use RNA sequencing and systematically mine produced data to select applicants based for testing. We will specifically focus on transcription factors and genes that are upregulated following dendrite injury. These applicants will be tested and confirmed in our dendrite regeneration assay. Identification of genes required for dendrite regeneration will greatly enhance our understanding of dendrite regeneration. It will allow investigation of dendrite regeneration in other models and disease-specific contexts. Additionally, discovery of genes required for dendrite regeneration will represent a first step in determining how well conserved dendrite regeneration is on a molecular level.
Dendrite regeneration is a neuronal survival mechanism that has recently gained attention. Limitations in current understanding prevent us from known the role of dendrite regeneration in neurological diseases. This research will discover molecular features of dendrite regeneration to bridge this gap in knowledge.
