Inhalation of combustion smoke causes mortality and morbidity with immediate and delayed neurological impairments in survivors. In the current environment with escalating threats of terrorism, chemical warfare and combat situations, the risk of severe exposure to combustion smoke has significantly increased. Thus the expanding scope of the problem necessitates urgent development of therapies to reduce neuropathology and long terms needs for care and rehabilitation. The development of targeted neuroprotective strategies however, is hindered since the molecular mechanisms underlying smoke inhalation neurotoxicity are not well defined. To understand the progression of neurotoxic events triggered by smoke inhalation, we developed a combustion-smoke inhalation model in the conscious rat. Our preliminary data demonstrate that the rat brain transcriptome and mitochondrial proteome are significantly altered by inhalation of smoke. Transcriptome changes peak at 24 hours and subside within seven days post smoke injury. Overall, changes indicate concomitant activation of injurious and protective processes,with marked upregulation of genes involved in stress, cell death and protein degradation. In addition, we detect formation of oxidative damage in nuclear and mitochondrial DMA,and a delayed loss of hippocampal neurons several weeks after inhalation of smoke. We hypothesize that smoke inhalation impairs the fidelity of mtDNA repair and replication and that resultant, compromised integrity of the mitochondrial genome leads to dysfunction and loss of hippocampal neurons. To test this hypothesis we have planned experimentswith the following Specific Aims: 1) To delineate the effects of smoke inhalation on the oxidative DMAdamage repair process in the brain. 2) To characterize smoke inhalation-induced alterations of the mitochondrial proteome, and determine to what extent mitochondria-encoded proteins are regulated at the transcriptional level and reflect loss of mitochondrial genomic integrity. 3) To elucidate mechanisms by which hyperbaric oxygen affects targets of smoke inhalation in the brain. Since our model is designed to mimic a real life situation, hyperbaric oxygen therapy, often given to smoke victims, is examined with respect to potential for protection of specific molecular and cellular targets of smoke. The overall objective of our proposal is to identify neurotoxic mechanisms contributing to delayed neuropathology in survivors of smoke inhalation. Our approach takes advantage of the novel rat model of smoke inhalation and integrates genomic and proteomic approaches to identify molecular mechanisms involved in the initiation and progression of smoke inhalation neurotoxicity, with the goal to establish a foundation for targeted neuroprotective therapies.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
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Neurotoxicology and Alcohol Study Section (NAL)
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Kirshner, Annette G
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University of Texas Medical Br Galveston
Schools of Medicine
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Zhuo, Ming; Gorgun, Murat F; Englander, Ella W (2017) Translesion Synthesis DNA Polymerase Kappa Is Indispensable for DNA Repair Synthesis in Cisplatin Exposed Dorsal Root Ganglion Neurons. Mol Neurobiol :
Zhuo, Ming; Gorgun, Murat F; Englander, Ella W (2016) Augmentation of glycolytic metabolism by meclizine is indispensable for protection of dorsal root ganglion neurons from hypoxia-induced mitochondrial compromise. Free Radic Biol Med 99:20-31
Gorgun, Falih Murat; Zhuo, Ming; Singh, Shilpee et al. (2014) Neuroglobin mitigates mitochondrial impairments induced by acute inhalation of combustion smoke in the mouse brain. Inhal Toxicol 26:361-9
Singh, Shilpee; Zhuo, Ming; Gorgun, Falih M et al. (2013) Overexpressed neuroglobin raises threshold for nitric oxide-induced impairment of mitochondrial respiratory activities and stress signaling in primary cortical neurons. Nitric Oxide 32:21-8
Englander, Ella W (2013) DNA damage response in peripheral nervous system: coping with cancer therapy-induced DNA lesions. DNA Repair (Amst) 12:685-90
Singh, Shilpee; Englander, Ella W (2012) Nuclear depletion of apurinic/apyrimidinic endonuclease 1 (Ape1/Ref-1) is an indicator of energy disruption in neurons. Free Radic Biol Med 53:1782-90
Lee, Heung Man; Greeley Jr, George H; Englander, Ella W (2011) Transgenic overexpression of neuroglobin attenuates formation of smoke-inhalation-induced oxidative DNA damage, in vivo, in the mouse brain. Free Radic Biol Med 51:2281-7
Deng, Xiaoling; Vidal, Ruben; Englander, Ella W (2010) Accumulation of oxidative DNA damage in brain mitochondria in mouse model of hereditary ferritinopathy. Neurosci Lett 479:44-8
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Li, Hui; Swiercz, Rafal; Englander, Ella W (2009) Elevated metals compromise repair of oxidative DNA damage via the base excision repair pathway: implications of pathologic iron overload in the brain on integrity of neuronal DNA. J Neurochem 110:1774-83

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