[R35] Defining the Role of Aminoacyl-tRNA Synthetases in Human Health and Disease
Ente: National Institute of General Medical Sciences
Scadenza: 2030-06-30
Importo max: 415.451 EUR
Paese: US
Descrizione
PROJECT ABSTRACT
Aminoacyl-tRNA synthetases (ARSs) are a ubiquitously expressed, essential class of enzymes responsible for
ligating amino acids to cognate tRNA molecules. Importantly, all 37 loci encoding an ARS have been
implicated in dominant and/or recessive clinical phenotypes, making these enzymes a major contributor to
human inherited disease. It is now important to systematically assess the role of ARS alleles in human disease
phenotypes and to determine how they affect gene function and cellular homeostasis. These data will provide
insight into the molecular pathology of disease-associated ARS alleles, which affect a wide range of tissues.
Furthermore, defining the molecular mechanisms of ARS-associated diseases will allow rapid patient diagnosis
through distinguishing pathogenic from non-pathogenic alleles in human populations. We and others have
shown that disease-associated ARS alleles cause a loss-of-function effect on tRNA charging. However, the
goals for the next five years are to address a number of critical, unanswered questions, including: (1) What is
the full complement of pathogenic ARS alleles in dominant and recessive disease? (2) What distinguishes
pathogenic versus non-pathogenic ARS variants? (3) How are ARS loci regulated? and (4) What is the
complete repertoire of ARS functions in mammalian cells? Here, we employ multiple established and
complementary model systems—computational, biochemical, cellular, yeast, worm, and mouse—to address
the above questions. Combined, the areas of study outlined in this proposal will improve our understanding of
ARS biology and allow us to define how certain ARS alleles give rise to dominant and/or recessive human
diseases. Furthermore, the breadth of the proposed studies—including both foundational and applied basic
science—will facilitate the professional development of laboratory members, and will result in a sustainable
research program.
Istituzione: UNIVERSITY OF MICHIGAN AT ANN ARBOR
PI: Anthony Antonellis
Progetto: 5R35GM136441-07
Settori: National Institute of General Medical Sciences
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