Research in the lab is focused on the biology of the endosomal/lysosomal (E/L) system, with particular focus on the defects underlying Niemann-Pick Type C (NPC) disease. NPC disease is a rare autosomal recessive lipidosis whose patients exhibit progressive neurodegeneration and hepatosplenomegaly, leading to death during early childhood. The majority of NPC patients carry mutations in NPC1, which encodes a large late endosomal transmembrane protein whose exact function remains unclear. Several studies have shown that NPC1 cells have a generalized transport block from late endosomes to the trans-Golgi network (TGN), suggesting that the NPC1 protein functions to facilitate vesicle movement and/or fusion with target membranes such as the TGN.

Work in our lab has shown that telomerase (TeRT)-immortalization of cells from NPC1 patients results in the correction of the cellular lipid storage phenotype. Furthermore, these effects on the E/L system are independent of NPC1 protein function, suggesting that TeRT-immortalization produces changes that are responsible for the alteration of specific lipid transport pathways from the E/L system to the TGN and plasma membrane. Characterization of these protein/gene expression changes as they relate to the function of the E/L system will yield new clues regarding the mechanisms and regulation of these pathways.

Another focus of our research is the development of new paradigms for the treatment of NPC and other lysosomal storage disorders (LSDs) with neuropathology. LSDs such as NPC result from a partial or total lack of a specific protein. There are only two ways to replace a missing or malfunctioning protein: 1) provide/introduce the protein exogenously as in enzyme/protein replacement therapy, or 2) introduce the gene encoding the necessary protein by gene therapy. Both of these approaches are not currently suitable for disorders with neuropathology due to the inaccessibility of the brain resulting from the blood-brain barrier. Our studies provide a new strategy for the identification of pharmacologically relevant molecules with the potential for treatment of NPC1 disease, which should also be applicable to many other lysosomal diseases with neuropathology that preclude the application of straightforward treatment options.