php@caltech.edu
Ph.D. 1970, Johns Hopkins University
more on Paul H. Patterson...
Interactions Between the Nervous and Immune Systems
Much of the research in this laboratory involves the study of
interactions between the nervous and immune systems. Using knockout
mice and over-expression in vivo with viral vectors, we are exploring
the role of the neuropoietic cytokine leukemia inhibitor factor (LIF) in
regulating neural stem cell proliferation and fate in the adult brain.
In the context of neuroimmune interactions during fetal brain
development, we are investigating a mouse model of mental illness based
on the known risk factor of maternal influenza infection. Huntington's
disease (HD) is another focus, where we are investigating potential
therapies using intracellular expression of antibodies (intrabodies) and
also manipulating NFkB activity. We are also studying the regulation
of MeCP2 by IKKa, because MeCP2 mutations are responsible for Rett
syndrome, which frequently involves autism symptoms.
Cytokines
are diffusible, intercellular messengers that were originally studied
in the immune system. Our group contributed to the discovery of a
family that we termed the neuropoietic cytokines, because of their
action in both the nervous and hematopoietic/immune systems. We
demonstrated that one of these cytokines, LIF, can coordinate the
neuronal, glial and immune reactions to injury. Using both delivery of
LIF in vivo and examination of the consequences of knocking out the LIF
gene in mice, we find that this cytokine has a powerful regulatory
effect on the inflammatory cascade. Moreover, LIF can regulate
neurogenesis and gliogenesis. LIF is a critical regulator of astrocyte
and microglial activation following stroke, seizure or trauma, and this
cytokine also regulates inflammatory cell infiltration, neuronal and
oligodendrocyte death, gene expression, as well as adult neural stem
cell renewal. These results highlight LIF as an important therapeutic
target. We are currently examining the role of LIF in a chemical model
of multiple sclerosis, where exogenous LIF can increase oligodendrocyte
number and stimulate remyelination.
Cytokine involvement in a
model for mental illness is also being investigated. This mouse model
is based on findings that maternal infection can significantly increase
the likelihood of schizophrenia and autism in the offspring. We are
using behavioral, neuropathological, molecular, and brain imaging
methods to investigate the effects of activating the maternal immune
system on fetal brain development and how this leads to altered behavior
in young and adult offspring. The cytokine IL-6, acting on both the
placenta and fetal brain, is key in mediating the effects of maternal
immune activation (MIA) on the fate of the offspring. We have new
evidence that MIA alters the endogenous immune cells in the placenta, as
well as lymphocyte reactions to stimulation in the adult offspring. In
collaboration with the Mazmanian laboratory at Caltech, we are also
examining the effects of MIA on gastrointestinal tract inflammation in
the offspring.
We are utilizing intracellular antibody
expression to block the toxicity of mutant huntingtin (Htt), the protein
that causes HD. We produced single-chain intrabodies that bind to
various domains of Htt, and these can either exacerbate or alleviate Htt
toxicity in cultured cells, acute brain slices, and in Drosophila HD
models. Recent findings indicate that viral delivery of one of these
intrabodies in five different mouse models of HD is highly effective in
ameliorating the behavioral deficits and neuropathology caused by mutant
Htt in these models. We have also implicated the NFkB signaling
pathway in the pathogenesis of HD, and identified several steps in this
signaling cascade as potential therapeutic targets. In collaboration
with the Langen laboratory at USC, using electron paramagnetic resonance
spectroscopy we have obtained new structural information on the domains
of mutant Htt when it forms fibrils.
Selected Publications for Paul H. Patterson
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