| Budget Amount *help |
¥18,720,000 (Direct Cost: ¥14,400,000、Indirect Cost: ¥4,320,000)
Fiscal Year 2015: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
Fiscal Year 2014: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000)
Fiscal Year 2013: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
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| Outline of Final Research Achievements |
Selective vulnerability in motor neuron (MN) subtypes is a fundamental aspect of amyotrophic lateral sclerosis (ALS). MNs are subdivided into three motor units; fast-fatigable (FF), fast fatigue-resistant (FR) and slow (S). In ALS, FF MNs are more vulnerable than FR and S MNs. We found that the extracellular matrix (ECM) protein osteopontin (OPN) is selectively expressed by FR and S MNs, whereas matrix metalloproteinase-9 (MMP-9) is expressed by FF MNs. OPN is accumulated as extracellular granules in ECM in ALS mouse models and a familial ALS case. In SOD1G93A mice, OPN/MMP-9 double positivity marks remodeled FR and S MNs destined to compensate for lost FF MNs before ultimately dying. Genetic ablation of OPN in SOD1G93A mice shows dichotomic effects; disease onset is delayed but disease progression is accelerated. OPN induced MMP-9 up-regulation via αvβ3 integrin. Our results demonstrate that OPN is involved in the second-wave neurodegeneration by up-regulating MMP-9 in ALS.
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