Browsing by Subject "central nervous system (CNS)"

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    GABAA Receptor Subunit Expression in Early Adolescent Mice
    (Office of the Vice Chancellor for Research, 2013-04-05) Anuebunwa, Nonso; Colar, Delphine; Boehm, Stephen L., II
    Gamma-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian central nervous system (CNS). Of the known receptors for GABA, the pentameric GABAA receptor appears to mediate fast GABA neurotransmission in the CNS. A number of different GABAA receptor subunits have been described to date, including α1-6, β1-3, γ1-2, and δ, with the specific functionality of any one receptor dictated by the combination of subunits. Although much is known about the pattern of GABAA subunit expression across the adult brain, the pattern of such expression during the critical developmental period of adolescence, which is a time of rapid neurobiological, hormonal, and behavioral change, remains largely unknown. GABAA receptor systems play a key role in normal neural, hormonal, and behavioral function, warranting a basic understanding of adolescent-specific alterations in the pattern of subunit expression. The current project focuses on determining the pattern of mRNA expression of GABAA receptor subunits in early adolescent (postnatal day 30) versus adult (postnatal day 65) mice. The prefrontal cortex, hippocampus, nucleus accumbens, midbrain, amygdala and cerebellum were harvested at these two ages; thus far the midbrain has been the focus due to the presence of the ventral tegmental area and its well-known role in motivation, reward and drug addiction. Midbrain tissue was processed for determination of GABAA receptor subunit mRNA expression using RT-PCR. We predict that early adolescence will be associated with a unique pattern of GABAA receptor subunit expression, suggesting an important role for GABAA receptors in the neurobiological, hormonal, and behavioral profile of this developmental period in mice. Preliminary findings indicate an increase in GABAA delta subunit expression in the adult midbrain.
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    GILZ-mimics as novel therapeutic agents for progressive multiple sclerosis
    (Office of the Vice Chancellor for Research, 2013-04-05) Srinivasan, Mythily; Dunker, K. A.; Lahiri, Debomoy K.; Pollok, Karen E.
    Multiple sclerosis (MS), a leading cause of neurological disability is an inflammatory demyelinating disease of the central nervous system (CNS). The clinical course of MS is highly variable ranging from isolated neurologic episodes to frequently relapsing or progressive disease. Currently there are no effective treatments for progressive MS. The long-term goal of this project is to evaluate a novel therapeutic strategy for progressive MS. Under physiological conditions signaling via the transcription factor, nuclear factor-kappa B (NF-κB) and glucocorticoid (GC) stimulation pathways regulate the immuno-inflammatory responses of the CNS resident glial cells. While NF-κB induces transcriptional activation, signaling via GC receptor functions to suppress immune responses. Persistent activation of NF-κB in the glial cells precipitates neuronal degeneration and axonal loss characteristic of progressive MS. Interactome analysis between the GC and NF-κB pathways suggested a novel strategy to inhibit NF-κB. Glucocorticoid-induced leucine zipper (GILZ) is a GC inducible protein that binds p65, the functionally critical subunit of NF-κB, and prevent transactivation of pathological mediators. The sites of interaction are localized to the proline rich region of the GILZ protein and the p65 transactivation domain. A 23 residue GILZ peptide prevented nuclear translocation of p65 and suppressed disease in an animal model of MS. Structurally GILZ peptide adopted polyproline type II (PPII) helical conformation, a favorable feature for drug development. The objective of this study is to optimize the lead peptide and develop drug like analogs. Specific features of the GILZ-p65 interactions were adapted in the design of over 25 GILZ analogs such that each exhibit optimum PPII helix, bind p65 transactivation domain and potentially accommodate modified residues that enhance the binding specificity with the p65. The analogs were ranked after passing through the Lipinski filter to determine the drug like properties. The top ranked analogs will be evaluated for functional efficacy.