Research
The Role of Protein Synthesis Enzymes in Complex Human Diseases
My research group has been investigating the biology of tRNA and aminoacyl-tRNA synthetases (ARSs) for nearly three decades. Seminal contributions resulting in high impact papers include the first description of minimal tRNA substrates (mini- and microhelix); the characterization of identity elements in the tRNA acceptor stem; the discovery of mechanistic distinctions between class I and class II ARSs, including substrate assisted catalysis; the first characterizations of an aminoacyl-tRNA synthetase-like protein (HisZ) with a function distinct from aminoacylation; determination of the kinetic basis of amino acid editing mechanisms; and more recent work on characterization of ARS alleles associated with diseases of peripheral and central nervous system. In collaboration with Karen Lounsbury, we found that threonyl-tRNA synthetase (TARS) is secreted from endothelial cells and promotes angiogenesis in both a cellular and organismal context. In collaboration with investigators from Franklin and Marshall College, we discovered that mutations in the gene encoding human histidyl-tRNA synthetase (HARS) are genetically linked to type IIIb Usher Syndrome. We discovered that the Usher Syndrome mutation confers temperature sensitivity on the mutant protein, potentially leading to ER stress, unfolded protein response, and neuronal death. Over the last 8-10 years, we have developed extensive collaborations worldwide to characterize additional mutant ARS alleles associated with both peripheral neuropathies and CNS neurodevelopmental disorders. Our recent work has featured extensive collaborations with Alicia Ebert (University of Vermont), an expert in eye development who employs zebrafish as a model organism. In future work, we hope to leverage our experience in the HARS-associated inherited eye disease Usher Syndrome Type 3 to investigate the role ARSs as nutritional sensors in neurogenesis, employing zebrafish eye development as the key model system.