There is keen interest in identifying the biochemical pathways that promote tumor intracerebral infiltration since members of these pathways serve as potential therapeutic targets. Unfortunately, the spatiotemporal nature of these pathways renders the application of conventional tools (over/under-expression of the proteins of interest, inhibitory compounds, etc.) inadequate for studying dynamic cell behavior. We seek to engineer and evaluate optogenetic analogs of cofilin, cofilin?s upstream activators (slingshot and chronophin), and cofilin?s upstream negative regulators (LIM protein kinase, the cAMP-dependent protein kinase, the p21 activated protein kinase, and rho-associated protein kinase). These species offer a means to correlate spatially-focused biochemical activity with dynamic cellular behavior including F-actin remodeling activity as well as migratory and invasive aptitudes.
The proposed research program seeks to elucidate the biochemical basis of cellular motility and migration in neurological diseases, with a focus on metastatic invasion. We have developed an approach to genetically engineer light-responsive proteins implicated in the biochemical pathways that drive aberrant behavior and we seek to correlate signaling activity at specific intracellular sites with cellular phenotype.
