This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Proinflammatory events in the brain promote activation of microglia which release ligands for glutamate receptors, including glutamate itself. Excitotoxic NMDA receptors require binding of a second ligand to a distinct site. Traditionally, the agonist of this second site is glycine, but recent evidence points to an in vivo role for D-serine. D-serine is formed by Serine Racemase (S-Race), an enzyme that isomerizes L-serine to D-serine. S-Race is induced in microglia in response to inflammatory stimuli such as the Alzheimer's amyloid b-peptide and lipopolysaccharide (LPS). This expression of S-Race in response to proinflammatory stimuli suggests a possible mechanism to explain the connection between inflammation, pain and neurodegeneration. Several S-Race mRNA isoforms have been described, each with a unique promoter, but producing transcripts with one common translation start site. Preliminary data generated by the P.I. suggest that only isoform d is expressed in microglia in response to LPS stimulation. Previous data from the mentor's lab have identified a functional LPS- responsive AP-1 binding site in intron 1c, the region upstream of isoform d. Although isoform b is the major transcript in normal brain, similar studies of sequences upstream of isoform b indicate that this isoform is not responsive to LPS stimulation. These results suggest that the promoters of S-Race are differentially regulated, with isoform b having a basal promoter, and isoform d having an LPS-responsive promoter via its AP-1 element.
The aims of this proposal seek to clarify the dilemmas surrounding the expression of the S-Race isoforms, and explore the relationship between its functional transcriptional elements and Alu sequence. The S-Race gene spans ~21kb, consisting of eight exons separated by introns with highly repetitive Alu sequence. Interestingly, the functional AP-1 element is embedded within Alu sequence in intron 1c. The association between active transcriptional elements and Alu sequences has only recently begun to be recognized.
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