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Research Description

Labeling for Newly Synthesized Arc mRNA
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Labeling for Newly Synthesized Arc mRNA

Hippocampal Neuron in Low Density Culture
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Hippocampal Neuron in Low Density Culture		 Excitotoxic Cell Death in the Hippocampus
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Excitotoxic Cell Death in the Hippocampus

  Primary Research Interests
Genetic determinants of cellular responses to injury. Our research program uses a forward genetic approach to define the cellular processes that occur after injury that lead either to progressive degeneration on the one hand or cellular repair on the other. This approach takes advantage of inbred strains of mice that carry genes that cause fundamentally different cellular responses to injury. Using these mice, we then focus on experimental models that exemplify progressive degeneration or cellular repair.

In the course of studies of genes that control cellular responses to injury, we made two discoveries that motivate current work: A) certain inbred strains of mice do not exhibit progressive tissue necrosis and cavitation following spinal cord injury, and instead exhibit a unique wound healing response; B) the same strains of mice are invulnerable to at least one form of excitotoxic cell death, whereas other strains exhibit the same vulnerability as rats. The fact that certain strains of mice do not exhibit progressive necrosis and cavitation is of considerable importance for studies of spinal cord injury. In the first place, these findings demonstrate that progressive necrosis and cavitation are not inevitable consequences of spinal cord injury in mammals. Hence, mice appear to have solved a problem that is considered a prerequisite to promoting axonal regeneration (eliminating progressive necrosis and cavitation). For this reason, mice will provide an enormously useful experimental platform with which to explore strategies to enhance axonal regeneration. Both discoveries indicate that genetic factors do affect the initial cellular responses to spinal cord trauma, and that these differences lead to substantial differences in the overall cellular cascades induced by the injury. Thus it should be possible to use genetic approaches to dissect out the molecular cascades that are responsible for these differences. This information should provide clues about how to manipulate the early responses and so prevent progressive necrosis and cavitation in other species. Indeed, it may be possible to develop treatment strategies that mimic the effects of the genes so as to enhance repair.

Current experiments address a number of specific questions:
  1. To what extent does which the elimination of progressive necrosis and cavitation in the injured spinal cord create a tissue environment that is favorable to neuronal survival, axonal regeneration, and functional recovery.
  2. Does invulnerability to excitotoxic cell deat reduce the extent of secondary degeneration following spinal cord injury;
  3. What cellular and molecular mechanisms are responsible for the invulnerability to excitotoxic cell death in certain strains of mice?
A second major component of our research focuses on the mechanisms underlying mRNA sorting and transport in neurons. During early development, when neurons are actively growing their axons and dendrites, there is a massive transport of certain mRNAs into the growing processes. In dendrites, these mRNAs are thought to play a key role in providing a substrate for local synthesis of key protein constituents of synapses. In axons, the mRNAs are selectively transported into "growth cones" which are the leading edge of the growing axon. Our working hypothesis is that vigorous axon growth depends on the presence of certain key mRNAs in the growth cone. Hence, our research program focuses on the basic mechanisms that underlie mRNA transport in neurons.

More About Dr. Steward's Work:
Research Description   Highlighted Publications   Biography   Reeve-Irvine Research Center

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