C. elegans transporters in neuronal function

Project Details

Description

DESCRIPTION (provided by applicant):
Glutamate is an excitatory neurotransmitter essential for function of the
nervous system. Certain injurious conditions cause excess glutamate to
accumulate at the synapse, resulting in hyperstimulation of the post-synaptic
neuron that can cause cell death. Glutamate transporters play an essential role
in neuronal health and function by removing excess glutamate from the synaptic
cleft. Considerable evidence implicates defective glutamate transport in ALS.
It is particularly striking that approximately 65% of sporadic ALS patients
have been reported to express aberrant glutamate transporter transcripts in
affected neurons, a phenotype correlated with inhibition of glutamate
transport.

We propose to conduct a thorough analysis of glutamate transporter mutations in
the facile C. elegans model system. The genome of this animal (sequenced to
completion) encodes six glutamate transporter genes. We will determine when,
and in which cells, the transporters are expressed, we will characterize their
biochemical properties, and we will determine the loss of function phenotypes
of each. We will also analyze the effects of expressing aberrant transporter
transcripts, analogous to some produced in ALS patients, in transgenic animals.
Finally, we will exploit the full power of C. elegans genetic analysis to
conduct screens for new mutations that reverse or modify transporter defects.
Genes identified in these screens should advance understanding of both normal
and aberrant glutamate signaling.

Since the C. elegans model system offers several unique advantages and most
biological processes are conserved, we expect that results of the proposed
study should provide new insight into basic mechanisms of Glu regulation at the
synapse and may suggest novel strategies for preventing neurodegeneration in
ALS.
StatusFinished
Effective start/end date7/1/016/30/05

Funding

  • National Institute of Neurological Disorders and Stroke: $194,375.00
  • National Institute of Neurological Disorders and Stroke: $194,375.00
  • National Institute of Neurological Disorders and Stroke: $194,375.00
  • National Institute of Neurological Disorders and Stroke: $192,155.00

ASJC

  • Medicine(all)
  • Neuroscience(all)
  • Genetics
  • Biochemistry, Genetics and Molecular Biology(all)
  • Molecular Biology

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