Hypoxia-ischemia encephalopathy (HIE) remains a leading cause of severe brain damage that occurs in 0.1-0.2% of term or near-term infants, among whom approximately 20% die and up to 40% of the survivors often suffer devastating disabilities. To date, no effective clinical treatment is available to mitigate brain damage and improve the brain functional development of these children. Insulinlike growth factor I (IGF-I) is a pleiotrophic factor essential for the development of the mammalian nervous system. IGF-I reduced brain damage and improved the survival of hypoxic-ischemic rats and fetal sheep. Recently, we found that exogenous IGF-I was more effective in reducing hypoxic-ischemic brain injury and in improving functional behavior development,13 if given after 24 hours of recovery. We hypothesize that, in the delayed phase of hypoxia-ischemia recovery, IGF-I treatment will promote brain repair by (1) reducing delayed neuronal apoptosis;and (2) stimulating neuro- and oligodendrogenesis and revascularization. We will examine this novel hypothesis using complementary in vitro and in vivo models of hypoxia-ischemia.
Aim 1 will characterize the mechanisms by which IGF-I prevents or reduces delayed neuronal apoptosis following hypoxia-ischemia.
Aim 2 will investigate if and how IGF-I stimulates revascularization and neuro-/oligodendrogenesis following neonatal hypoxiaischemia. Results of this investigation will provide crucial information towards establishing an effective therapy for newborn patients suffering from hypoxicischemic encepholapathy.
How the proposed work meets the goals/requirements of the ARRA? The proposed work will be performed in four laboratories at the Indiana University School of Medicine, involving one principal investigator and three co-principal investigators. In addition, the proposed experiments will be conducted by a highly trained research scientist, a postdoctoral fellow, and a research analyst. All three individuals have advanced degrees (2 also have M.D.) and have been working on biomedical research for more than five years. Over the past several years, they have made significant contributions to the preliminary work that led to the original and revised applications. There is no doubt that saving their jobs would help sustain not only this research project, but also contribute to the future development of effective therapies for brain injuries. A key component of the proposed experiments is combined immunohistochemistry. To collecting preliminary data, we had to obtain permission to use equipment from another laboratory located in another building after work. To ensure the successful completion of the proposed and future experiments, we requested funds to purchase an Olympus BX51fluorescence microscope with a DP71 camera (budgeted in the first year only at $38,000). Designated to this project, this piece of equipment will greatly facilitate the progress of the proposed work. Can the work generate meaningful results within two years? We are confident that, if completed, the proposed work will generate meaningful results within two years. In particular, we have all cell cultures and animal models in place and all personnel are well trained to carry out the proposed experiments. Our preliminary data demonstrated that we worked through technical difficulties in combining immunocytochemistry, transfecting primary neurons, and obtaining critical reagent. We have also established a working relationship with collaborators, such as Dr. Stallcup, an expert in oligodendrogenesis. With a detailed working plan and experimental designs, there is little doubt that the results of this revised project will generate crucial information concerning the mechanisms of IGF-I in brain repair following hypoxia-ischemia to newborn brains. Furthermore, the results of this investigation will lay the ground work for IGF-I based therapies for other brain injuries and neurodegerative diseases. How do the new specific aims relate to the ones that went through peer review? The two specific aims in the modified application are derived from two of three aims in the original application (1 R01 HD-059979-01A 1). In particular, the new Aim 1 is the original Aim 2 and the new Aim 2 is the original Aim 3. The original application was discussed by the Neural Oxidative Metabolism and Death Study Section (NOM D) on February 2, 2009, and received a priority score of 186 (22.3%).
| Rong, Zhihui; Pan, Rui; Chang, Liwen et al. (2015) Combination treatment with ethyl pyruvate and IGF-I exerts neuroprotective effects against brain injury in a rat model of neonatal hypoxic-ischemic encephalopathy. Int J Mol Med 36:195-203 |
| Pan, Rui; Rong, Zhihui; She, Yun et al. (2012) Sodium pyruvate reduces hypoxic-ischemic injury to neonatal rat brain. Pediatr Res 72:479-89 |
