Summary
Developmental and Regenerative Neurobiology
Our group engages in advanced research in developmental and regenerative neuroscience from the molecular to cell biological and integrative levels. Major interests pertain to the chemotactic guidance of neural cells during embryonic development and neuropathogenesis. Long-term goals are to determine how chemotropic cues in the microenvironment guide nerve growth, and how dysfunctional guidance mechanisms cause disease. Our NIH-funded research is currently defining the spatiotemporal signal transduction mechanisms by which nerve growth cones detect extracellular guidance cues and dynamically regulate cellular effectors to control the direction of axon extension during normal embryonic development (Project 1) and neural regeneration after injury (Project 2). Recent advances provide molecular insights into how cues elicit local phosphoinositide and ionic calcium signals in the growth cone and in turn regulate the distribution of substrate adhesions to establish a plane of asymmetry during chemotactic guidance. Longer term, we aim to define mechanisms for priming and guiding regenerating axons to appropriate synaptic targets to complete functional circuits. Within these themes, specific topics under investigation include:
- molecular analysis of guidance receptors and signal transduction mechanisms,
- gradient sensing and axon guidance,
- regulated endocytosis and exocytosis, and
- functional regulation of cell adhesion molecules.
A related topic under investigation is the molecular mechanisms mediating the invasiveness of Glioblastoma multiforme (GBM), which is the most common and aggressive primary brain tumor. These highly invasive astrocytomas can rapidly infiltrate the brain, rendering GBM incurable by surgical resection. The invasion pattern follows selective tracts, and most recurrent GBMs arise either locally or within regions that are connected to the primary site by these tracts, suggesting that chemotropic guidance cues may regulate invasive GBM cell migration. Our goal is to develop experimental and potentially therapeutic strategies by focusing on the specific biological cues that control the invasiveness of these tumors (Project 3).