IR-INDUCED APOPTOSIS IN THE DEVELOPING NERVOUS SYSTEM

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DESCRIPTION (adapted from applicant's abstract): Brain tumors are second only to leukemia as the most prevalent form of pediatric malignancy. However, unlike leukemia, effective treatments for brain tumors are lacking. Ionizing radiation is one of the more common strategies used to treat brain tumors. While radiation can be effective in killing the tumor, a devastating consequence of this approach is damage to normal tissues, resulting in severe cognitive impairment. It has been estimated that upward of 60 percent of children treated for brain tumors by irradiation develop significant cognitive defects. The damaging effects of radiation upon both tumor and normal tissue are likely to involve apoptosis. The prevention of damage to normal tissue as well as radiosensitizing the tumor would have significant clinical impact. Both scenarios would benefit from a comprehensive understanding of the regulatory components operating during apoptosis. Therefore, a detailed molecular understanding of the apoptotic process will afford the opportunity for therapeutic intervention and the clinical control of these processes. Research described in this proposal will elucidate critical components of the ionizing radiation induced apoptotic pathway in the nervous system, thereby facilitating a greater understanding of the molecular interplay involved. Additionally, this research will also provide fundamental information about the role of death regulators in the nervous system. The investigator's preliminary data show that new gene expression is required for IR-induced apoptosis in the developing nervous system. The PI will use cDNA microarray analysis, representational difference analysis and protein interaction analysis to determine which genes are causal in IR-induced damage of the early postnatal nervous system. The PI will subsequently focus the analysis of these genes by selecting those that are regulated in wildtype mice, but not in mice such as Atm or p53-null, with defective IR-induced neural apoptosis. Using a variety of in vitro and in vivo approaches, they will determine the contribution of these IR-induced genes towards apoptosis in the nervous system. Identifying and characterizing the genes involved in cell death will be valuable for rational design of approaches to manipulate these processes clinically. Moreover, as neurodegenerative disease may engage similar apoptotic pathways, the findings from this proposal will be relevant for understanding neuronal death in neurodegenerative disease.