Proteostasis broadly describes all processes which work to maintain protein balance within the cell, including synthesis, folding, and degradation. Our lab investigates how proteostasis differs between species, an area which has important implications for therapeutic development in model systems.
Protein Trafficking
Our group was the first to identify differences in protein trafficking between mouse and human NPC1. Interestingly, these differences were observed despite mouse and human proteins sharing 86% identity and 93% similarity. Importantly, we also demonstrated that these differences drive differential therapeutic response. We hypothesize that previous efforts to use proteostatic modulators as therapeutic agents for Niemann-Pick type C disease have been confounded by these species-specific differences in protein trafficking. We are actively investigating what are the molecular and regulatory pathways causing these differences.
Model Generation
The development of effective therapeutics for human patients will require the generation of models which mimic human NPC1 proteostasis better than current mouse models. To address this need, our group has developed a panel of isogenic induced pluripotent stem cells (iPSCs) harboring various disease-causing mutations in NPC1. By inducing transcription factor expression, we can rapidly and efficiently differentiate the iPSCs into excitatory neurons over a period of five days. This system allows us to study potential therapeutics in a disease relevant cell type. Continued efforts to develop additional iPSCs lines are underway.