TRUSTEES OF INDIANA UNIVERSITY
Grant: $364,480 - National Institutes of Health - Sep. 17, 2009
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Award Description: Cerebral hypoxia-ischemia during the perinatal period is the single most important cause of acute newborn mortality and chronic disability. Despite our increasing understanding of the mechanisms of neuronal injury, an effective clinical therapy has yet to be established to mitigate brain damage and improve the prognosis and well being of these newborn patients. IGF-I is a well-known neurotrophic factor, essential for the survival and functional maturation of immature neurons. Previously, IGF-I's effects on hypoxia-ischemia induced damage were evaluated using a neonatal hypoxia-ischemia model. Even with large doses of IGF-I infused intraventricularly immediate following hypoxia-ischemia, the reduction of hypoxic-ischemic brain damage was only 40% at one week of recovery. On the other hand, we recently demonstrated that subcutaneous administration of IGF-I at 24 and 48 hours of recovery significantly reduced hypoxia-ischemia induced injury to immature rat brains and improved their long-term memory and cognitive behavior. Therefore, IGF-I's therapeutic efficacy seems to depend on the timing of administration. Based on our preliminary data, we hypothesize that, immediately following hypoxia-ischemia, oxidative stress renders neurons unresponsive to IGF-I's trophic activities which, combined with decreased circulating IGF-I levels and neuronal IGF-I expression, contributes to the imminent neuronal death. We further hypothesize that, in later phase of recovery, IGF-I reduces hypoxia-ischemia induced injury to immature brains by inhibiting delayed apoptosis and by stimulating neuro- and oligodendrogenesis as well as revascularization. We will test these hypotheses in vitro using primary neuronal cultures derived from newborn rats and in vivo using an established neonatal rat model for HIE. Aim 1 will determine whether oxidative stress-induced neuronal IGF-I resistance contributes to hypoxia- ischemia induced acute neuronal death. Aim 2 will characterize the mechanisms by which IGF- I prevent or reduces hypoxia-ischemia induced delayed neuronal apoptosis. Aim 3 will investigate if and how IGF-I stimulates revascularization and neuro- /oligodendrogenesis following neonatal hypoxia-ischemia. Results of this investigation will not only evaluate a novel mechanism of neuronal death but also evaluate IGF-I's clinical use for the treatment of hypoxic- ischemic encephalopathy.
Project Description: Based on our preliminary data, we hypothesize that, immediately following hypoxia-ischemia, oxidative stress renders neurons unresponsive to IGF-I's trophic activities which, combined with decreased circulating IGF-I levels and neuronal IGF-I expression, contributes to the imminent neuronal death. We further hypothesize that, in later phase of recovery, IGF-I reduces hypoxia-ischemia induced injury to immature brains by inhibiting delayed apoptosis and by stimulating neuro- and oligodendrogenesis as well as revascularization. We will test these hypotheses in vitro using primary neuronal cultures derived from newborn rats and in vivo using an established neonatal rat model for HIE. Aim 1 will determine whether oxidative stress-induced neuronal IGF-I resistance contributes to hypoxia- ischemia induced acute neuronal death. Aim 2 will characterize the mechanisms by which IGF- I prevent or reduces hypoxia-ischemia induced delayed neuronal apoptosis. Aim 3 will investigate if and how IGF-I stimulates revascularization and neuro- /oligodendrogenesis following neonatal hypoxia-ischemia. Results of this investigation will not only evaluate a novel mechanism of neuronal death but also evaluate IGF-I's clinical use for the treatment of hypoxic- ischemic encephalopathy.
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