Science Background

The type, duration and amplitude of cell stress signals that are activated by a chemical determine the ultimate fate of the cell. The current picture of how toxicants affect cells is one in which toxicant-induced damage can elicit different effects depending on the type of damage, the concentration of the toxicant and the type of cell involved. In general, lower toxicant concentrations trigger signalling that elicits adaptive responses that allow cells to better tolerate the chemical insult.

At higher concentrations toxicants induce signalling that eventually results in regulated cell modalities. Regulated cell deaths involve the activation of a genetically encoded molecular machinery as exemplified by apoptosis. At even higher toxicant concentrations poisoning of critical cellular macromolecules causes an overall loss of cellular homeostasis and an unregulated necrosis. This cell death is unregulated as the cell plays no active role in its own demise. In this case, the toxicant induced molecular signature reflects dysfunction in signalling pathways and the signalling is not required for cell death.

There must be critical differences in the molecular signatures of each of these fates (toxicant adaptive responses, toxicant regulated cell death responses, toxicant unregulated necrosis), but these difference are either poorly defined or unknown.

Knowledge Gaps  

  1. What are the molecular signatures induced by myotoxicants and how do the signatures change with time and concentration?
  2. What are the molecular signatures induced by caspase-3 activity during death and differentiation?
  3. Can molecular signatures be used to predict cell adaptation, cell dysfunction and/or cell death?