""""""""Mechanisms of Neuronal Death and Neuroprotection"""""""" Chemotherapeutic neurotoxins provide model systems in which basic cellular mechanisms relevant to human disease can be studied. Findings can lead directly to design of treatment trials. Neurotoxicity is dose limiting for cis-diamminedichloroplatinum (cisplatin; CDDP), a first line agent for treating ovarian, testicular, and other neoplasms. The primary target is the dorsal root ganglion (DRG) neuron or its axon. We have demonstrated in a rat model that CDDP induces apoptosis in DRG and have replicated this process in vitro. Nerve growth factor (NGF) prevents this cell death. In cancer cells CDDP binds to DNA. Dividing cells respond to DNA damage by slowing or arresting growth allowing the cell to repair damage before proceeding to DNA replication. If DNA damage is extensive, the cell undergoes apoptosis. The investigators have previously demonstrated that CDDP induces apoptosis in neurons. This is preceded by up regulation of nuclear cyclin D1 expression and increased phosphorylation of the retinoblastoma gene product. These biochemical changes and ceil death are prevented by nerve growth factor (NGF). They propose that DNA damage in neurons induces repair processes that up regulate genes associated with transition from G0 to G1. Since it is highly disadvantageous for post-mitotic neurons to divide, they undergo apoptosis. We will test this hypothesis by (1) determining whether CDDP induces DNA damage by forming Pt-DNA adducts in DRG neurons and whether Pt-DNA complexes are sufficient to induce apoptosis; (2) determining which steps in DNA damage recognition or repair are necessary to initiate cisplatin induced neuronal death using mouse knockouts. If they are necessary, do they occur upstream of the cell cycle changes? (3) Determine where NGF interrupts the death pathway and which NGF signal transduction pathway is responsible for rescue. NGF can be used therapeutically as a specific neuroprotectant. It is one of the primary survival factors for DRG neurons, it has been safely administered to humans, systemic NGF has access to DRG neurons in vivo, and most cancer cells do not have NGF receptors. In the future we will determine whether NGF can be used therapeutically in animal and human models of GDDP neurotoxicity. We will also determine whether the effects of NGF are shared by the other DRG growth factors, brain derived neurotrophic factor (BDNF), and neurotrophin-3 (NT3).
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