| 研究実績の概要 |
To study the in vivo and in vitro effects of Parkin loss-of-function, we used a mouse model of CNS inflammation (MOG-induced experimental autoimmune encephalomyelitis (EAE) model). We showed that Parkin deficiency alterates the glia-mediated innate immunity, modulating the inflammatory process during EAE, eventually resulting in exacerbation of clinical symptoms. An increased number of encephalitogenic CD8αβ+TCRαβ+ T cells and γ/δ T cells, together with a massive infiltration of macrophage/microglia, were detected in the periphery and in the CNS of Parkin-/- mice with enhanced tissue-damaging effect.
Moreover, we have identified Pink1 and Parkin as potential biomarkers to distinguish patients with MS in the acute phase from patients with other neuroinflammatory disorders.
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| 現在までの達成度 (区分) |
現在までの達成度 (区分)
1: 当初の計画以上に進展している
理由
Considering the role of neuroinflammation in neurodegenerative disorders such as Parkinson’s disease, the aim of our study was to elucidate the effects of the mitophagy-related gene Parkin on neuroinflammation. Since Immune reactivity to astrocytes is associated with several neurological conditions, we studied the functional heterogeneity of astrocytes, using for the first time MOG-induced EAE, as a model of acute central nervous system inflammation, in Parkin knockout mice, who display impairment of astrocytes. Moreover, as mitochondrial dysfunction is known to contribute to neuroinflammation, neurodegeneration, and axonal damage, we elucidated the important role of mitophagy-related proteins, PTEN-induced kinase 1 (Pink1) and Parkin, in the etiology of neuroinflammatory and neurodegenerative diseases observed in Japanese patients.
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| 今後の研究の推進方策 |
1)To study the role of astrocytes in in EAE by using other animal models of CNS-specific autoimmune neuroinflammatory disease: C57BL/6N-Gbatm1.1Mjff/J (PD, Gaucher, synucleinpathies), C57BL/6N Pink1-/- (Parkinson's disease).
2)Tio study the impact of aging on glial immune response by using the following strain: Parkin -/- mice young (<3 months); Parkin -/- mice mature-adult (3-6 months; Parkin -/- mice aged (6-9 months); neonatal mice
3)To study the neuroprotective effect of BCG (vaccination) in EAE, and the mechanism behind the modulation of the glial immune response.
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