Despite detailed understanding of the cellular mechanisms leading to neuronal death following acute injury, acute brain injury is an important cause of neurologic disability in patients for which there is no treatment. I have found that F-68, a tri-block co-polymer of polyethylene and polypropylene, profoundly rescues neurons from severe injury in vitro and in vivo, by repairing the loss of neuronal plasma membrane integrity. Targeting the plasma membrane with this polymer constitutes a novel, effective, and potentially important treatment for rescuing neurons following acute injury. The major objective of this application is to understand how tri-block co-polymers interact with damaged membranes to rescue injured neurons. To achieve this objective, we will study the interactions of these co-polymers with increasingly complex membrane systems: giant unilamellar vesicles (GUVs), sealed erythrocyte ghosts and cultured hippocampal neurons.
The Specific Aims of this proposal are: 1) Identify the role played by co-polymer architecture in the efficacy of membrane repair and the importance of co-polymer architecture in neuroprotection. 2) Identify the role played by lipid packing density in inducing F-68 insertion into and repair of the plasma membrane. 3) Identify the role played by co- polymers in decreasing oxidative stress and peroxidative plasma membrane damage during acute injury. 4) Identify the role played by membrane lipid peroxidation and changes in membrane fluidity in inducing F-68 insertion into and repair of the plasma membrane.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS056313-03
Application #
7640679
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Hicks, Ramona R
Project Start
2007-05-15
Project End
2012-04-30
Budget Start
2009-07-01
Budget End
2010-06-30
Support Year
3
Fiscal Year
2009
Total Cost
$333,534
Indirect Cost
Name
University of Chicago
Department
Pediatrics
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Wang, Janice C; Bindokas, Vytautas P; Skinner, Matthew et al. (2017) Mitochondrial mechanisms of neuronal rescue by F-68, a hydrophilic Pluronic block co-polymer, following acute substrate deprivation. Neurochem Int 109:126-140
Plant, Leigh D; Marks, Jeremy D; Goldstein, Steve An (2016) SUMOylation of NaV1.2 channels mediates the early response to acute hypoxia in central neurons. Elife 5:
Muller, Aaron J; Marks, Jeremy D (2014) Hypoxic ischemic brain injury: Potential therapeutic interventions for the future. Neoreviews 15:e177-e186
Shelat, Phullara B; Plant, Leigh D; Wang, Janice C et al. (2013) The membrane-active tri-block copolymer pluronic F-68 profoundly rescues rat hippocampal neurons from oxygen-glucose deprivation-induced death through early inhibition of apoptosis. J Neurosci 33:12287-99
Waypa, Gregory B; Marks, Jeremy D; Guzy, Robert D et al. (2013) Superoxide generated at mitochondrial complex III triggers acute responses to hypoxia in the pulmonary circulation. Am J Respir Crit Care Med 187:424-32
Sabharwal, Simran S; Waypa, Gregory B; Marks, Jeremy D et al. (2013) Peroxiredoxin-5 targeted to the mitochondrial intermembrane space attenuates hypoxia-induced reactive oxygen species signalling. Biochem J 456:337-46
Waypa, Gregory B; Osborne, Scott W; Marks, Jeremy D et al. (2013) Sirtuin 3 deficiency does not augment hypoxia-induced pulmonary hypertension. Am J Respir Cell Mol Biol 49:885-91
Wang, Jia-Yu; Marks, Jeremy; Lee, Ka Yee C (2012) Nature of interactions between PEO-PPO-PEO triblock copolymers and lipid membranes: (I) effect of polymer hydrophobicity on its ability to protect liposomes from peroxidation. Biomacromolecules 13:2616-23
Plant, Leigh D; Zuniga, Leandro; Araki, Dan et al. (2012) SUMOylation silences heterodimeric TASK potassium channels containing K2P1 subunits in cerebellar granule neurons. Sci Signal 5:ra84
Plant, Leigh D; Dowdell, Evan J; Dementieva, Irina S et al. (2011) SUMO modification of cell surface Kv2.1 potassium channels regulates the activity of rat hippocampal neurons. J Gen Physiol 137:441-54

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