The endoplasmic reticulum (ER) is the intracellular organelle in which secretory and membrane proteins are synthesized and folded by resident chaperone proteins. The ER stress response (ERSR) is an evolutionarily conserved cell defense mechanism that protects against excessive accumulation of malfolded proteins in the ER. These malfolded proteins are translocated to the cytoplasm by the machinery of the ER- associated degredation (ERAD) where they are degraded. The ERSR is initiated after multiple cellular stresses including hypoxia, inflammation, trauma, excitotoxicity, and oxidative damage. The ERSR is initially protective, but if malfolded proteins cannot be cleared, apoptotic cell death initiates. The 3 pathways involved in the ERSR involve PERK, IRE1/XBP-1, and ATF6 signaling. Preliminary data demonstrate upregulation of all 3 ERSR pathways following SCI. Mice null for CHOP, a pro-apoptotic transcription factor that is downstream of PERK and activated during ERSR, showed enhanced functional recovery after SCI and we identified oligodendrocytes as highly vulnerable to ER stress. We hypothesize that enhancing the protective or inhibiting the apoptotic aspects of the ERSR will enhance functional recovery after SCI.
In Aim 1, we will potentiate the protective effectors of ERSR and in Aim 2 suppress those that initiate oligodendrocyte apoptosis. We will use a combination of pharmacological agents, constitutive and conditional null mice, as well as cell culture studies using wild type (WT) and available null oligodendrocyte precursor cells (OPCs) and/or siRNAs to address these questions.

Public Health Relevance

Spinal cord injury (SCI) is a devastating injury for both patients and their families and at present, there is no effective treatment, either acutely or for chronic patients. This grant examines the role of the endoplasmic reticulum stress response, a cellular defense mechanism induced in every spinal cord cell after SCI, in mediating survival or death of myelinating oligodendrocytes after SCI. We expect to identify new acute therapeutic targets that will hopefully extend beyond SCI to other CNS trauma and neurological disease treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS073584-04
Application #
8610955
Study Section
Acute Neural Injury and Epilepsy Study Section (ANIE)
Program Officer
Jakeman, Lyn B
Project Start
2011-02-01
Project End
2016-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Louisville
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
City
Louisville
State
KY
Country
United States
Zip Code
40202
Slomnicki, Lukasz P; Hallgren, Justin; Vashishta, Aruna et al. (2018) Proapoptotic Requirement of Ribosomal Protein L11 in Ribosomal Stress-Challenged Cortical Neurons. Mol Neurobiol 55:538-553
Saraswat Ohri, Sujata; Mullins, Ashley; Hetman, Michal et al. (2018) Activating Transcription Factor-6? Deletion Modulates the Endoplasmic Reticulum Stress Response after Spinal Cord Injury but Does Not Affect Locomotor Recovery. J Neurotrauma 35:486-491
Vashishta, Aruna; Slomnicki, Lukasz P; Pietrzak, Maciej et al. (2018) RNA Polymerase 1 Is Transiently Regulated by Seizures and Plays a Role in a Pharmacological Kindling Model of Epilepsy. Mol Neurobiol 55:8374-8387
Kilanczyk, Ewa; Andres, Kariena R; Hallgren, Justin et al. (2017) Pharmacological inhibition of spinal cord injury-stimulated ribosomal biogenesis does not affect locomotor outcome. Neurosci Lett 642:153-157
Slomnicki, Lukasz P; Pietrzak, Maciej; Vashishta, Aruna et al. (2016) Requirement of Neuronal Ribosome Synthesis for Growth and Maintenance of the Dendritic Tree. J Biol Chem 291:5721-39
Slomnicki, Lukasz P; Malinowska, Agata; Kistowski, Michal et al. (2016) Nucleolar Enrichment of Brain Proteins with Critical Roles in Human Neurodevelopment. Mol Cell Proteomics 15:2055-75
Pietrzak, Maciej; Rempala, Grzegorz A; Nelson, Peter T et al. (2016) Non-random distribution of methyl-CpG sites and non-CpG methylation in the human rDNA promoter identified by next generation bisulfite sequencing. Gene 585:35-43
Kilanczyk, Ewa; Saraswat Ohri, Sujata; Whittemore, Scott R et al. (2016) Antioxidant Protection of NADPH-Depleted Oligodendrocyte Precursor Cells Is Dependent on Supply of Reduced Glutathione. ASN Neuro 8:
Kilanczyk, Ewa; Filipek, Anna; Hetman, Michal (2015) Calcyclin-binding protein/Siah-1-interacting protein as a regulator of transcriptional responses in brain cells. J Neurosci Res 93:75-81
Vashishta, A; Hetman, M (2014) Inhibitors of histone deacetylases enhance neurotoxicity of DNA damage. Neuromolecular Med 16:727-41

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