Brain atrophy, otherwise classified as CNS neurodegeneration (CNS-ND), is a common feature of neurological diseases 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 brain atrophy 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 remains irreversible and has correlated with cognitive and motor deficits. Furthermore, the observation of brain atrophy being a feature of so many pressing neurological conditions necessitates the development of model systems to determine the cellular and molecular basis for CNS-ND. Our research team recently published the first study of CNS-ND using the Theiler?s virus model of primary progressive MS. In this proposal, we introduce a novel model of acute brain atrophy that presents in the FVB mouse strain. The discovery of CNS-ND in TMEV infected 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 during TMEV infection and have early onset brain atrophy. We propose to test our central hypothesis that neuroinflammation contributes to CNS-ND. Based on solid preliminary data, and through the use of our unique 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 that results in brain atrophy. The proposed research is innovative because it capitalizes on the first demonstration that brain atrophy is impacted by the immunologically relevant Db class I molecule. This strongly implies a role for specific types of inflammation, namely CD8 T cells, in promoting brain atrophy, a feature of neurological disease with unknown etiology. Furthermore, the proposed development of the transgenic mouse used will enable conditional silencing of the Db class I molecule expression in specific cell types in vivo. To accomplish these aims, we will employ: (a) flow cytometry, (b) behavioral studies, (c) high resolution confocal microscopy and immunohistochemistry, and (d) small mammal MRI and MR spectroscopy.
Brain atrophy, otherwise classified as CNS neurodegeneration (CNS-ND), is a common feature of neurological diseases 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. Our preliminary data suggests that inflammation contributes to brain atrophy in the Theiler?s murine encephalomyelitis virus model. Using unique transgenic mouse models of brain atrophy, we will determine the contribution of class I molecules and major immune cell types in the onset of brain atrophy.
| Malo, Courtney S; Huggins, Matthew A; Goddery, Emma N et al. (2018) Non-equivalent antigen presenting capabilities of dendritic cells and macrophages in generating brain-infiltrating CD8 + T cell responses. Nat Commun 9:633 |
| Huseby Kelcher, April M; Atanga, Pascal A; Gamez, Jeffrey D et al. (2017) Brain atrophy in picornavirus-infected FVB mice is dependent on the H-2Db class I molecule. FASEB J 31:2267-2275 |
