ID: 2187

• Title:
  Unexplored pathological consequences of electric field-induced damage to the nuclear environment
  
  Authors:
  

  Stacey, Michael. Center for Bioelectrics, Old Dominion University, Norfolk, Virginia, USA
  Vernier, Thomas, P. Center for Bioelectrics, Old Dominion University, Norfolk, Virginia, USA
  Muratori, Claudia. Center for Bioelectrics, Old Dominion University, Norfolk, Virginia, USAs

  
  
  Abstract:
  Pulsed electric field (PEF) applications in biomedicine are gaining attention, both as therapeutic modalities and in core methodologies. The use of lethal (tissue ablation) and non-lethal (neurostimulation, protein/matrix remodeling, and drug delivery) PEF is on the rise. In both lethal and non-lethal applications there are surviving cells — what are the consequences? PEF induces damage to the cytoskeleton, potentially untethering the nucleus from external environmental stimuli. In cells exposed to nanosecond-duration PEF (nsPEF) we observe nuclear swelling and nuclear envelope (NE) damage, hallmarks of diseases of the nuclear lamina. Diseases associated with lamin mutations, the laminopathies, are typically characterized by nuclear instability, abnormal cytoskeletal architecture, and defective nucleo-cytoskeletal transmission of cellular forces, leading to DNA damage, epigenetic modifications, and inflammatory response — all observed in cells exposed to PEF. Because the NE mediates regulation of nuclear architecture, DNA remodeling, and gene expression, and because nsPEF-induced degradation in nuclear organization occurs in parallel with changes in cytoskeletal configuration, it is reasonable to expect that these intracellular events can lead to or affect pathophysiology. The consequences of sublethal PEF-induced damage to the NE and to the cytoskeleton have not been fully described.
  
  Experiments underway will define previously uncharacterized effects of PEF exposures on the nucleus and cytoskeleton, focusing on 1. NE damage; 2. epigenetic changes to DNA; and 3. inflammatory responses. Measuring the ratio of heterochromatic histone methylation to euchromatic histone methylation will test the hypothesis that dissociation of lamin-bound heterochromatic DNA will skew the epigenetic profile.
  
  We are looking in PEF-exposed cells for laminopathy indicators of genome disorganization, to understand better the effects of PEF on cells, including sublethal treatments, and at the same time evaluating whether this can be a useful tool for the study of laminopathies. We propose that PEF will be a tool to investigate NE biomechanics, additionally acting as a model for studying pathogenic mechanisms of diseases of lamin.
  
  
  
  Keywords:
  nsPEF, Nuclear membrane, Laminopathy, Epigenetics, Inflammatory respnse
  
  Refs:
  
  
  Topic 1:
  1. Biological responses (molecular, subcellular, cellular and intercellular)
  
  Topic 2:
  12. Biomedical applications