Regulation of cell fate and function by sterol homeostasis
Defining the mechanisms and molecular interactions underlying progenitor specification to functional neural cell types is critical for understanding normal neurodevelopmental and disease process. Mutations disrupting enzymes which catalyze cholesterol synthesis are known to cause malformation syndromes characterized by reduced cholesterol and cholesterol precursor accumulation. Though mutated enzymes are expressed broadly across tissues and disorders exhibit commonalities (cholesterol deficiency, dysmorphologies, developmental delay, and reduced lifespan), neural specific phenotypes vary across these disorders. Precisely how and why cholesterol metabolism exerts specific effects on cellular mechanisms and signaling pathways to affect stem cell activity, neurodevelopment and cellular function is unclear. Aim 1 of this proposal is to determine the cellular outcomes and signaling changes stemming from disruption of sterol homeostasis. These studies will delineate sterol specific effects on neural fate choice and identify the hierarchical changes in transcriptional and lipid signaling leading to altered cell fate. Aim 2 will define protein-protein interactions reliant on sterol homeostasis, how sterol disruption affects protein-protein interactions, and define the functional consequences in neural cell types leading to changes in functional activity. These studies will detail mechanistic effects of sterol disruption of developmentally critical signaling pathways. These studies will ultimately define the effects of sterol protein interactions on developmental signaling, work that will fundamentally impact our understanding of the mechanisms underlying regulation of neurodevelopment and cellular function by cholesterol homeostasis.
Anderson, RH., Francis, KR. (2018) Modeling rare diseases with induced pluripotent stem cell technology. Mol Cell Probes. PMID:29307697
This project is supported by the NIH-funded Center for Biomedical Research Excellence, Center for Pediatric Research