Inborn Errors of Purine Metabolism: Developing a C. elegans model to uncover molecular mechanisms driving neuromuscular, behavioral and developmental phenotypes

Project: Research project

Project Details


? DESCRIPTION (provided by applicant): Multiple Inborn Errors of Purine Metabolism are associated with devastating neurological and behavioral phenotypes. Both the lack of purine biosynthesis and the abnormal accumulation of intermediary metabolites upon perturbation of purine biosynthetic enzyme function are proposed to contribute to neurological dysfunction. However, the precise etiology of neurological symptoms associated with these disorders has remained elusive. This proposal for a small research grant is focused on establishing the C. elegans model for the study of Inborn Errors of Purine Metabolism with the overarching goal of identifying the links between perturbed purine metabolism and neurological dysfunction. Aim 1 is to identify the specific perturbations driving discrete phenotypes for one specific disorder, Adenylosuccinate Lyase (ADSL) Deficiency, providing proof of principle for the usefulness of the system as a model of Inborn Errors of Purine Metabolism. Both genetic and pharmacological approaches will be used to establish causal relationships between purine metabolite level or de novo purine biosynthetic pathway function and distinct neuromuscular, developmental or behavioral phenotypes. Because the experiments in the first aim are designed to manipulate phenotypic outcome by manipulating metabolite and pathway function, an expected outcome is generation of novel ideas for therapeutic intervention in neuromuscular, developmental and behavioral phenotypes. Aim 2 is to measure changes in the purine-related metabolome during development to determine the demands for purines during ontogenesis. This analysis will be paired with genetic experiments to functionally probe the developmental requirements for de novo purine biosynthesis. The purpose of the ontogenic analysis is to shed light on why disorders of purine biosynthesis have phenotypes that are believed to arise from lack of purine biosynthesis and yet patients show no deficit in purine levels. The hypothesis is that deficits in availability of purines during development are relevant to phenotypic outcome. The final aim is to use global metabolomics profiling as a discovery based approach to fill in the black box between the metabolic changes identified in Aim 1 as causative of a specific phenotype and the mechanism driving phenotypic output. The outcome of the proposed work includes the generation of ideas for novel therapeutic approaches to ADSL deficiency and analysis of the purine metabolome and its dynamics during development to lay the foundation for deciphering the mechanisms whereby purine metabolism affects neurological function.
Effective start/end date4/1/169/30/18


  • National Institute of Neurological Disorders and Stroke: $75,263.00
  • National Institute of Neurological Disorders and Stroke: $75,391.00


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