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Richard Kraig,
M.D., Ph.D. |
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My
research centers on deciphering how the brain can protect itself against
neurological disease. The brain is unique among organ structures. It can
alter its regional, cellular and molecular structure in response to activity.
This classically is evidenced by Hebbian synaptic
plasticity but it also extends to environmental enrichment (i.e., increased
intellectual, social, and physical activity), which protects brain against neurodegeneration. The mechanisms by which naturally
increased brain activity strengthens brain are largely unknown. Deciphering
the bases by which increased brain from environmental enrichment alters both
the form and function of brain has immense clinical value since environmental
enrichment reduces subsequent neurological disease by half without negative sequelae. Our work,
and that of others, shows that learning involves increased production of
tumor necrosis factor alpha (TNF-α), one a group of innate cytokines,
typically recognized for their involvement as early responders to disease. Furthermore,
our work shows that neuroprotection from activity
depends on intrinsic production of TNF-α. This is an adaptive change
that requires time to develop and extinguishes if not maintained by activity.
Cytokines, including TNF-α, alter tissue structure and function by
altering gene expression of related transcription factors, growth factors and
anti-apoptotic genes. TNF-α and the other innate cytokines are highly pleiotropic and interactive. Accordingly, we have
developed cell-specific genomic and proteomic techniques to acquire the
“vocabulary” needed to understand the “syntax” of
activity-dependent neuroprotection via the
application of computational analysis strategies. We use in vitro and in vivo animal models of epilepsy, stroke, aging, and migraine as
our exemplary diseases for study. We use cellular and molecular imaging
strategies as well as genomic and proteomic techniques and computational
analyses of data from these approaches to search for the “signaling
syntax” by which natural neural activity makes brain more resilient to
disease. Our tools include real-time cellular imaging, laser dissection
microscopy, real-time RT-PCR, semi-quantitative cellular cytological and immunohistochemical imaging, all proteomic tools
(including bead-based, multiplexed ELISAs), and nanoparticle gene delivery systems now in development. Specific Research Projects: 1. The mechanisms and consequences of
spreading depression 2. The mechanisms by which brain
activity results in neuroprotection 3. How sleep modulates
activity-dependent neuroprotection 4. How cold generates neuroprotection 5. Development and use of nanoparticle-based gene delivery for epilepsy treatment 6. Development and use of macrophage-nanoparticle gene delivery systems for treatment of brain
disease Research can also be viewed at kraiglab.uchicago.edu
A partial listing of Dr. Kraig's published work can be seen via Medliine, a database maintained by the National Library of Medicine. Hulse RE, |
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