| Budget Amount *help |
¥19,500,000 (Direct Cost: ¥15,000,000、Indirect Cost: ¥4,500,000)
Fiscal Year 2010: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000)
Fiscal Year 2009: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000)
Fiscal Year 2008: ¥7,280,000 (Direct Cost: ¥5,600,000、Indirect Cost: ¥1,680,000)
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| Research Abstract |
In this study, we have examined the neuronal death mechanism underlying Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). We also performed basic and translational research to search for endogenous neuroprotective factor Humanin.
1, The presenilin(PS)1/PS2 involvement of TGFβ2-induced neuronal death via APP. We found that PS1/PS2 are essential for TGFβ2-induced neuronal death via APP. MOCA is the key molecule that unifies APP-mediated death signal to PS-mediated death signal.
2. Identification of EH as an endogenous agonist of Humanin. We found that EH is a far more potent endogenous agonist of Humanin. EH, injected intracerebraventricularly or intraperitoneally, showed anti-AD-related dementia activity in vivo. A series of experiments also showed that EH, highly expressed in skin tissues, is transported across blood-brain barrier to the central nervous system. These results suggest that EH play a main role in inhibiting AD-related neuronal death and dysfunction in vivo as a physiological defense factor.
3. Fishing of small chemicals mimicking Humanin. We found that a couple of small chemicals induced the oligomerization of the Humanin receptor subunits. This result confirmed that they have Humanin activity.
4. Preclinical test of Colivelin, a potent Humanin derivative. We found that intranasally administered Colivelin was efficiently transported to the central nervous system without modification or cleavage.
5. The ALS pathogenesis. We clarified the detailed mechanism underlying P56SVAPB-induced ALS form the standpoint of unfolded protein response. We also found that low-grade overexpression of TDP-43 induces motor neuron death mediated by the upregulation of Bim and the downregulation of Bcl-xL. TDP-43-induced death is attenuated by its cleavage by activated caspases. We finally found that BTBD-10-deficient C. elegans showed death of touch neurons and motor abnormality.
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