ABSTRACTBrain atrophy, otherwise classified as CNS neurodegeneration (CNS-ND), is a common feature of neurologicaldiseases as diverse as Alzheimer's disease, cerebral palsy, dementia, Pick?s disease, Huntington's disease,Krabbe disease, multiple sclerosis (MS), Epilepsy, Encephalitis, Neurosyphilis, and neuroAIDS. How brainatrophy occurs in neurological diseases remains to be fully defined. However, neuronal impairment, infection,and neuroinflammation have been put forward as putative mechanisms of CNS-ND. CNS-ND overall remainsirreversible and has correlated with cognitive and motor deficits. Furthermore, the observation of brain atrophybeing a feature of so many pressing neurological conditions necessitates the development of model systems todetermine the cellular and molecular basis for CNS-ND. Our research team recently published the first studyof CNS-ND using the Theiler?s virus model of primary progressive MS. In this proposal, we introduce a novelmodel of acute brain atrophy that presents in the FVB mouse strain. The discovery of CNS-ND in TMEVinfected FVB mice enables the use of powerful transgenic approaches to define the etiology of brain atrophy.Transgenic FVB mice that express the H-2Db (Db) class I molecule gain a new CD8 T cell response duringTMEV infection and have early onset brain atrophy. We propose to test our central hypothesis thatneuroinflammation contributes to CNS-ND. Based on solid preliminary data, and through the use of ourunique methodology, models, and reagents, we plan to pursue the following two aims:Specific Aim #1 ? Determine the extent CNS-ND is mediated through CD8 T cell responses.Specific Aim #2 ? Define the specific CNS cell type required to express the Db class I molecule thatresults in brain atrophy.The proposed research is innovative because it capitalizes on the first demonstration that brain atrophy isimpacted by the immunologically relevant Db class I molecule. This strongly implies a role for specific types ofinflammation, namely CD8 T cells, in promoting brain atrophy, a feature of neurological disease with unknownetiology. Furthermore, the proposed development of the transgenic mouse used will enable conditionalsilencing of the Db class I molecule expression in specific cell types in vivo. To accomplish these aims, we willemploy: (a) flow cytometry, (b) behavioral studies, (c) high resolution confocal microscopy andimmunohistochemistry, and (d) small mammal MRI and MR spectroscopy.
|Effective start/end date||6/1/16 → 5/31/18|
- National Institutes of Health: $238,500.00