The ability to detect extra-cellular stimuli and execute appropriate responses is crucial to all cellular functions. Neurons are specialized, morphologically complex cells that represent the functional unit of the nervous system. Neurons are equipped to respond to a variety of cues that direct proper intercellular wiring during development and the maintenance of long lasting synaptic changes during adult life. Mature neurons that have lost the ability to respond adequately to physiological cues or have became unable to overcome stressful stimuli undergo degenerative changes that result in abnormal function and eventually death. Neurotrophins comprise a family of peptide growth factors that sculpt the vertebrate nervous system by regulating cell growth, survival, proliferation and differentiation. One key nuclear target of neurotrophin signalling is the transcription factor CREB. I have previously shown that CREB plays a central role in mediating neurotrophin functions, supporting survival and growth of peripheral neurons.
However, the mechanisms by which neurotrophins regulate such diverse responses and the nature of the underlying nuclear changes are still largely unknown. I have recently obtained preliminary data that a novel, neurotrophin-regulated red ox signalling pathway is involved in modulating nuclear responses in neurons under physiological conditions. In particular, neurotrophin-dependent synthesis of nitric oxide and reactive oxygen species (ROS) regulate gene expression by inducing CREB-DNA binding and initiation of transcription.
The goals of this project are:
1) To characterize the early events leading to neurotrophin-dependent regulation of redox signalling in neurons.
2) To identify the nuclear targets and the nature of posttranslational modifications occurring upon neurotrophin-regulated nitric oxide and ROS synthesis.
3) To investigate the potential role of nitric oxide in modulating key transcriptional events during neuronal development.
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