Studies in my laboratory focus on the regulatory role of the Niemann-Pick C (NPC) disease genes in maintenance of cellular cholesterol homeostasis. Our work has shown that the Niemann-Pick C1 (NPC1) protein plays a critical role in delivery of lipoprotein (LDL)-derived cholesterol to the plasma…
more membrane and to the endoplasmic reticulum (ER). Our structure-function studies demonstrate that the sterol-sensing domain of the NPC1 protein regulates the trafficking of LDL cholesterol from endosomes. We have also shown that NPC proteins, in response to lipoprotein cholesterol, contribute to maintenance of cholesterol homeostasis through suppression of sterol regulatory element-binding protein (SREBP)-dependent gene expression as well as activation of liver X receptor (LXR)-mediated responses. The NPC proteins regulate these homeostatic responses through channeling of LDL cholesterol to sites of oxysterol synthesis, indicating that oxysterols play a central role in coordination of cellular cholesterol balance. In current studies we are using genetic approaches to isolate novel mutants with the NPC phenotype in order to dissect the steps required for the endocytic trafficking of cholesterol. Additionally, we are examining the role of the NPC proteins in development of atherogenesis in transgenic mouse models, and exploring therapeutic approaches aimed at prevention of cholesterol cytotoxicity in NPC disease.
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