|Budget Amount *help
¥14,200,000 (Direct Cost: ¥14,200,000)
Fiscal Year 2003: ¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2002: ¥4,600,000 (Direct Cost: ¥4,600,000)
Fiscal Year 2001: ¥6,500,000 (Direct Cost: ¥6,500,000)
Regeneration or cell replacement therapy has become one of the main topics in the field of cell biology due to remarkable advance of research in this field over the past decade. In particular, existence of endogenous neural stem cell or progenitors has been found in mature mammalian adult brain, which led to new approach to reconstruct lost neuronal network incurred by various insults through induction of neuronal regeneration from endogenous progenitors. In line with this concept, we addressed question whether neuronal regeneration can be induced in the hippocampal CA1 sector, a region supposed to be non-neurogenic, following ischemic neuronal death in rats. We found that neuronal progenitors exist in the periventricular region adjacent to CA1 sector, which respond to ischemia. Following administration of EGF and FGF-2 intraventricularly for 3 days after ischemia, we could successfully induce proliferation, migration and differentiation of neural progenitors in this region, resulting
in 40% recovery of neuronal population. In addition, these neurons displayed mature phenotype and extended dendrites and long axons. They finally re-established electrophysiological activity demonstrated by recovery of long-term potentiation, as well as improvement of cognitive function by assessing Marris Water Maze test. These findings imply that "non-neurogenic regions" still retain capacity for regeneration when stimulated by some factors after brain insults, and would open a new approach for various central nervous system disorders.
We also tried to establish an in vivo model of consistent ischemic neuronal injury in hippocampal CA1 in mice to explore molecular mechanisms of neuronal regeneration, since several gene modified animals are available in mice. In BL6 strain, we could produce this model by subjecting them to 14 minute ischemia through temporary occlusion of three vessels in the neck. This model would contribute greatly to understating of molecular control of progenitors in situ in the future research. Less