We are exploring the utility of C. elegans in studying conserved nutrient signalling pathways, including modeling rare human genetic disorders of metabolism. In collaboration with Dr. Semple (Univ of Cambridge, UK), we have initiated a proof-of-principle study using the DAF-2 insulin-like receptor in the worm to model mutations in the human insulin receptor (INSR). Combining bioinformatic analysis and in vivo assays, we tested mutations located throughout DAF-2 for phenotypic consequences and correlating those changes with human disease alleles. We have exploited the relatively quick and easy forward genetics, genome editing, and phenotypic assays of the C. elegans system to gain insight into human insulin receptor functional domains, including creating an allelic series of mutations in a single amino acid residue that mimics human disease severity. In collaboration with Iqbal Hamza's group (Univ of Maryland), we have continued to study how heme levels are sensed and regulated in animals using the C. elegans model system that provides unique advantages. During the past year, we completed a study of the heme-regulated gene number seven (HRG-7)that plays a role in inter-organ signalling and organismal heme homeostasis.
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