Molecular Biology of Oxidative Stress
I have had a longstanding interest in the free radical gas, nitric
oxide (NO), and its role in the central nervous system (CNS). Nitric
oxide, originally discovered as an environmental pollutant, is
synthesized at physiological levels by many mammalian cells and is
utilized for a variety of functions such as signal transduction for
cell signaling, for cellular differentiation, and for neurotransmission
in learning and memory. At a high flux rate, such as that released by
immune cells, or when released out of context in a stressed
environment, it has been established that NO is toxic. NO-mediated
damage is implicated in the cell death of motor neurons and their
support cells, oligodendrocytes, during CNS injury (stroke or spinal
transection) and during degenerative disease, such as Amyotrophic
Lateral Sclerosis (ALS), and Multiple Sclerosis (MS).
There are many proposed mechanisms and cellular targets of NO damage
with the major target being protein. High flux NO can disrupt
heme-containing proteins and cause them to release heme into the
intracellular environment. This has been proposed to result in
iron-mediated generation of reactive nitrogen species, namely
peroxynitrite. NO, when combined with other oxidants in the cell, forms
peroxynitrite which goes on to nitrate tyrosine residues, thereby
disrupting protein structure and function. Nitrotyrosine (3NY) positive
aggregates are seen in spinal injury and are found in the motor neurons
of ALS patients and in the plaques seen in MS patients. Due to my
research, and that of others, nitrotyrosine (3NY) is now regarded as a
quantifiable marker for NO-mediated damage in the CNS.
Induced Adaptive Resistance
Nitric oxide released at
physiological levels plays a variety of beneficial roles, while at high
doses or during pathological circumstances NO becomes toxic. I have
proposed that normal cellular resistance mechanisms are defective, in
the case of CNS disease, or overwhelmed, in the case of CNS injury. Is
it possible that these normal resistance mechanisms can be “primed”
against oxidative insult by a pretreatment dose of a lower
concentration of that oxidant? Specifically, I have asked if a low dose
of NO can prepare a cell for subsequent toxic challenge of NO or other
oxidants. In fact, I have discovered that cells pretreated with low
levels of NO become resistant to toxic levels of NO and other oxidants.
This phenomenon, Induced Adaptive Resistance (IAR), is dependent on
hemoxygenase1 (HO1), a heme-metabolizing enzyme.
Neuroengineering
My laboratory’s goal will be to continue in
our effort to develop a neural computer, the Neuristor™, using living
neurons. This computer will exploit all of the advantages of neurons.
Specifically, neurons rich with the nitric oxide (NO) dependent
learning receptor, N Methyl D Aspartate receptor (NMDAR), will be
utilized. These have previously been studied in the context of induced
adaptive resistance to NO (IAR). For the Neuristor™ we will take
advantage of the IAR phenomena since it has been demonstrated that IAR
neurons express more learning and memory receptors (NMDAR) as well as
increased neurite outgrowth. The neurons that we are currently using
are mammalian motor neurons. We are exploring the possibility of using
neurons derived from adult stem cells, and from bony fishes provided by
Bruce Stallsmith Ph.D. This laboratory has created a portable cell
culture incubator, the Cell Drive™ that is an ideal support structure
for the Neuristor™.
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