This is a competitive renewal with the broad objective of testing the Hypothesis: An autoimmune mechanism directed towards neuronal GluR subunits, associated with an inflammatory environment, contributes to neurodegenerative disorders such as Rasmussens encephalitis (RE). A hallmark of many neurodegenerative diseases is the extraordinary specificity through which disease progresses in the nervous system. In the past funding period we have examined immune dysfunction in this process through: 1) identifying autoantibodies to several GluR subunits in patients with neurodegenerative disease; 2) demonstrating their efficacy in directly altering receptor function; 3) identifying two mechanisms through which GluR antigens can escape tolerance; and 4) characterizing the interactions between autoantibodies and their target protein at the molecular and structural level. To determine how the inflammatory environment, as would be present in the microglial nodule, affects neuronal susceptibility to excitotoxicity, we developed a tissue culture system for exploring the mechanisms of cytokine-mediated changes in neuronal response. An ongoing aspect of this study is based upon the preliminary results that prolonged exposure of neurons to the inflammatory cytokine TNFalpha alters the expression of non-NMDA G1uR subunits. This renewal will continue to examine the neuronal response to an inflammatory environment and how this environment affects neuronal survival, both in response to excitotoxins and to anti- GluR antibodies as found in patients with RE and other neurodegenerative diseases.
In Specific Aims 1 and 2 we will determine the effects of inflammatory cytokines and microglia on neuronal remodeling of G1uR expression and function.
In Specific Aims 3 -5 we determine the mechanisms (including gene transcription, translation, assembly and degradation) that are used by the neuron to respond to the inflammatory environment and accomplish remodeling of GluR expression and function. Finally, in Specific Aims 6 and 7, we develop subunit-specific monoclonal antibodies (mAb) that act as highly specific GluR agonists and receptor modulators to determine their effect on neuronal viability when inflammation and subunit-specific agonist-like autoreactivity to GluRs occur simultaneously, as is present in RE.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS035181-08
Application #
6692581
Study Section
Special Emphasis Panel (ZRG1-BDCN-4 (01))
Program Officer
Stewart, Randall
Project Start
1997-01-01
Project End
2005-12-31
Budget Start
2004-01-01
Budget End
2004-12-31
Support Year
8
Fiscal Year
2004
Total Cost
$345,000
Indirect Cost
Name
University of Utah
Department
Genetics
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Nasertorabi, Fariborz; Alonso, Andres; Rogers, Scott W et al. (2005) Crystallization of the SH2-binding site of p130Cas in complex with Lck, a Src-family kinase. Acta Crystallogr Sect F Struct Biol Cryst Commun 61:174-7
Carlson, Noel G (2003) Neuroprotection of cultured cortical neurons mediated by the cyclooxygenase-2 inhibitor APHS can be reversed by a prostanoid. J Neurosci Res 71:79-88
Meyer, Erin L; Strutz, Nathalie; Gahring, Lorise C et al. (2003) Glutamate receptor subunit 3 is modified by site-specific limited proteolysis including cleavage by gamma-secretase. J Biol Chem 278:23786-96
Meyer, Erin L; Gahring, Lorise C; Rogers, Scott W (2002) Nicotine preconditioning antagonizes activity-dependent caspase proteolysis of a glutamate receptor. J Biol Chem 277:10869-75
Gahring, Lorise C; Rogers, Scott W (2002) Autoimmunity to glutamate receptors in the central nervous system. Crit Rev Immunol 22:295-316
Leibold, E A; Gahring, L C; Rogers, S W (2001) Immunolocalization of iron regulatory protein expression in the murine central nervous system. Histochem Cell Biol 115:195-203
Gahring, L; Carlson, N G; Meyer, E L et al. (2001) Granzyme B proteolysis of a neuronal glutamate receptor generates an autoantigen and is modulated by glycosylation. J Immunol 166:1433-8
Carlson, N G; Gahring, L C; Rogers, S W (2001) Identification of the amino acids on a neuronal glutamate receptor recognized by an autoantibody from a patient with paraneoplastic syndrome. J Neurosci Res 63:480-5
Rogers, S W; Gregori, N Z; Carlson, N et al. (2001) Neuronal nicotinic acetylcholine receptor expression by O2A/oligodendrocyte progenitor cells. Glia 33:306-13
Carlson, N G; Howard, J; Gahring, L C et al. (2000) RNA editing (Q/R site) and flop/flip splicing of AMPA receptor transcripts in young and old brains. Neurobiol Aging 21:599-606

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