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Faculty List
Paul H. Patterson
php@caltech.edu
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 (KO) mice and over-expression in vivo with viral vectors, we are exploring the role of neuropoietic cytokines in PNS and CNS injury and repair, Alzheimer's disease and inflammation. Also in the context of neuroimmune interactions, we are investigating a mouse model of mental illness based on the known risk factor of maternal influenza infection. We are also testing potential therapies for Huntington’s disease (HD), using intracellular expression of antibodies, and manipulating NFkB activity. An additional project involves the study of endothelin, cytokines and melanoma tumor progression.
Cytokines are diffusible, intercellular messengers that were originally studied in the immune system. Our group contributed to the discovery of a new family that we have termed the neuropoietic cytokines, because of their action in both the nervous and hematopoietic/immune systems. We have demonstrated that one of these cytokines, leukemia inhibitory factor (LIF), can simulatnaeously coordinate 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, both within and outside the nervous system. Moreover, LIF can regulate neurogenesis following injury. We find that LIF is a critical regulator of astrocyte and microglial activation following stroke, seizure or trauma, and that this cytokine also regulates inflammatory cell infiltration, neuronal and oligodendrocyte death, gene expression, as well as the production of new neurons from stem cells following injury. These results highlight LIF as an important therapeutic target. We are also examining the role of LIF in a transgenic mouse model of Alzheimer's disease to determine its effects on inflammation and cell proliferation, as well as on plaque formation and removal.
Cytokine involvement in a new model for mental illness is also being investigated. This mouse model is based on findings that maternal infection increases the likelihood of schizophrenia or autism in the offspring. We are using behavioral, neuropathological, molecular and brain imaging methods to investigate the effects of maternal influenza infection on fetal brain development, and how this leads to altered behavior in adult offspring.
We are utilizing intracellular antibody expression to block the toxicity of mutant huntingtin (Htt), the protein that causes HD. We have produced single chain antibodies (scFvs) that bind to various domains of Htt, and these can either exacerbate or alleviate Htt toxicity in cultured cells, acute brain slices, and in a Drosophila HD model. Work has begun on delivering these scFvs in mouse models of HD. 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.
