MECHANISMS OF NEURONAL DEATH AND NEUROPROTECTION

Project: Research project

Project Details

Description

DESCRIPTION(Adapted from the Investigator's Abstract): "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).
StatusFinished
Effective start/end date6/1/0012/31/11

ASJC

  • Medicine(all)
  • Neuroscience(all)