Status: Funded - Open
Walter Chen, MD, PhD
BACKGROUND: Metabolic organelles (e.g., mitochondria, peroxisomes) are essential for normal human physiology, as evidenced by the fact that mutations in genes encoding for organellar proteins can cause devastating pediatric disease. Organellar diseases are more common than previously thought with the prevalence of mitochondrial disease alone now estimated to be 1:5000 with ~2500 babies born with mitochondrial diseases in the US annually, similar to the number of babies born with the well-known genetic disorder cystic fibrosis. GAP: Our understanding of organellar proteins and consequently our knowledge of how organelles contribute to pediatric health and disease remains incomplete. To that end, we aim to identify and characterize proteins of unknown function associated with metabolic organelles. HYPOTHESIS: We hypothesize that a combined approach of proteomics, metabolomics, and clinical genomics will allow for the identification of these proteins. METHODS: Using proteomics, metabolomics, and clinical genomics, we will first identify uncharacterized proteins that may be organellar in nature and will prioritize them for further mechanistic study by the strength of association with pediatric clinical disease. Using this strategy, we have already identified numerous candidates and have begun successfully characterizing them using biochemical, metabolic, and cell culture approaches that will be complemented by mouse models. RESULTS: Pending. IMPACT: With the rising use of whole-genome sequencing to influence pediatric care and the incredible promise of modern-day gene therapies, it has become increasingly important to understand what uncharacterized organellar genes/proteins do so as to understand what genetic variants actually cause organellar disease. We thus believe this work can significantly influence the diagnosis and management of children with various metabolic disorders.