Neuronal-specific fatty acid synthesis activation as protective mechanism under hypoxia

University Of North Dakota, Grand Forks ND

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Abstract

Brain hypoxia is one of the major factors for loss of neuronal functions and viability in many disorders, including ischemic stroke and heart disease - the leading causes of death and long-term disability in the US. Our goal is to understand the mechanism underlying neuron adaptation to hypoxia to outline potentially new therapeutic target to increase innate protective mechanism in the hypoxic brain. To this end, we have identified in cultured cells, a novel, neuron-specific protective response to hypoxia that causes a dramatic activation of fatty acid synthesis from glutamate and glutamine. This suggests that activation of this mechanism under hypoxic conditions supports neuronal anaerobic metabolism through enhancing cellular reduction potential and by attenuating the level of glutamate and its downstream excitotoxicity. In the current application, we hypothesize that neuronal fatty acid synthesis is increased in the brain under hypoxia in vivo, and has a protective role against neuronal damage. We will test our hypothesis with the following Specific Aims: Specific Aim 1: Determine brain FAS alterations under hypoxia Using a validated hypoxia model, we will determine if hypoxia increases fatty acid synthesis in the whole brain of control mice and of mice with neuronal specifically attenuated fatty acid synthesis. Specific Aim 2: Determine protective role for neuronal FA synthesis under hypoxia 2.1. Using conditional knockout mouse model, we will validate the effect of neuronal specific fatty acid synthesis down-regulation under hypoxia. It is our expectation that FA synthesis down-regulation will worsen neuronal damage and associated biochemical outcomes under hypoxia. 2.2. Using pharmacological treatment, we will validate a hypothesized neuroprotective effect of fatty acid synthesis under hypoxia. Successful completion of these aims will test our novel mechanism for brain adaptation to hypoxia. This work is significant because glutamate release and altered reduction potential are the central mechanisms in CNS injury, and the proposed balancing of glutamate and reduction potential through fatty acid synthesis outlines innate protective mechanism. This work is innovative because it is a significant departure from the status quo and if successful, will identify a drug target to increase a novel, innate protective mechanism in the hypoxic brain under stroke, heart arrest, and other neurotraumatic injuries. In addition, the results will reveal a new function for neuronal fatty acid biosynthesis in regulation of neurotransmitters and brain energy metabolism.