Paul H. Patterson
Ph.D. 1970, Johns Hopkins University
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.
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.
Last modified 2013-02-04 01:27 PM