The long-term goal of the proposed research is to identify the mechanisms through which bidirectional communication between the nervous system and distal tissues regulates organism-wide responses to oxidative stress. Oxidative stress plays a critical role in cognitive dysfunction and neuronal death associated with neurodegenerative diseases. Nrf2 is a transcription factor that plays a key role in cellular resistance to oxidative stress, but little is known about the physiological signals that regulate Nrf2 activity in the brain or how Nrf2 impacts neuronal function. My laboratory uses the model C. elegans to study new signaling pathways that modulate presynaptic function. We recently identified the Nrf2 homolog, SKN-1, as a regulator of presynaptic structure and function. We found that SKN-1/Nrf2 functions cell non- autonomously to regulate neurotransmitter secretion from neuromuscular junctions. We also found that neuroendocrine signaling from the nervous system confers organism-wide protection from the toxic effects of oxidative stress by activating SKN-1/Nrf2 in distal tissues. Here we seek to uncover the cellular and molecular mechanisms by which bidirectional communication between the nervous system and distal tissues promotes an adaptive response to oxidative stress through the regulation of neurotransmitter secretion.
In Aim 1, we will determine how SKN-1/Nrf2 activity is positively regulated by neuropeptide release from the nervous system.
In Aim 2, we will determine how reactive oxygen species promote neuropeptide release in vivo.
In Aim 3 we will determine how synaptic transmission is negatively regulated by cell non-autonomous SKN-1 activation. Nrf2 activation protects neurons form death in a variety of neurodegenerative disease models, and our research may uncover new endogenous activators of Nrf2, which may lead to the development of new therapeutics that can prevent or treat these diseases.
Principal Investigator: Derek Sieburth Project Narrative Oxidative stress in the brain impacts synaptic function and neuronal survival and aberrant responses to oxidative stress are linked to neurodegenerative diseases and inflammation. Our research is focused on the fundamental mechanisms by which the Nrf2 oxidative stress response pathway is regulated by the nervous system and how Nrf2 signaling, in turn impacts synaptic function. Nrf2 activation protects neurons form death in a variety of neurodegenerative disease models, and our research may uncover new endogenous regulators of Nrf2 activity, which may lead to the development of new therapies that activate Nrf2.
| Kim, Sungjin; Sieburth, Derek (2018) Sphingosine Kinase Activates the Mitochondrial Unfolded Protein Response and Is Targeted to Mitochondria by Stress. Cell Rep 24:2932-2945.e4 |
| Kim, Sungjin; Sieburth, Derek (2018) Sphingosine Kinase Regulates Neuropeptide Secretion During the Oxidative Stress-Response Through Intertissue Signaling. J Neurosci 38:8160-8176 |
