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Neurotrophic factors are proteins that influence survival and function of neurons in the central and peripheral nervous systems. Recent studies, however, have shown that specific neurotrophic factors may cause neuronal death instead of survival, depending upon which receptors and signaling pathways are activated. We are examining mechanisms governing death- vs. survival-promoting actions of nerve growth factor and related neurotrophins during development and under inflammatory conditions.
Inflammation in the brain occurs as a consequence of trauma and in association with numerous neurologic diseases including neurodegenerative diseases such as Alzheimer's. Under inflammatory conditions, glial cells produce cytokines, which directly influence neuronal and glial function. Among the effects of inflammatory cytokines is regulation of neurotrophic factors, which critically influence survival and function of many neuronal and glial populations in the central nervous system. The interactions of cytokines and neurotrophic factors in the brain have important consequences for neuronal survival and function during disease.
Work in my lab investigates specific cellular mechanisms of cytokine and neurotrophin actions on CNS neurons and glia. We use primary cultures of embryonic neurons and glia to investigate mechanisms by which specific cytokines and trophic factors influence neuronal survival, and to identify stimuli that regulate production of cytokines and trophic factors. Our work is geared to understanding how these factors affect glial and neuronal function, and how they may ultimately influence neuronal survival under inflammatory conditions associated with disease in the brain.
B.A., Oberlin College, 1979.
Ph.D., The Rockefeller University, 1986.
Cragnolini, A.B., Volosin, M., Huang, Y.Y., and W.J. Friedman WJ. Nerve growth factor induces cell cycle arrest of astrocytes. Dev Neurobiol. 72(6):766-776, 2012.
Pichardo-Casas, I., Goff, L.A., Swerdel, M.R., Athie, A., Davila, J., Ramos-Brossier, M., Lapid-Volosin, M., Friedman, W.J., Hart, R.P., and L. Vaca. Expression profiling of synaptic microRNAs from the adult rat brain identifies regional differences and seizure-induced dynamic modulation. Brain Res. 1436:20-33, 2012.
Le, A.P., and W.J. Friedman. Matrix metalloproteinase-7 regulates cleavage of pro-nerve growth factor and is neuroprotective following kainic acid-induced seizures. J. Neurosci. 32(2):703-712, 2012.
Huang, Y.Y., Smith, D.E., Ibanez-Sandoval, O., Sims, J.E., and W.J. Friedman. Neuron-specific effects of Interleukin-1 beta are mediated by a novel isoform of the IL-1 receptor accessory protein. J. Neurosci. 31(49):18048-18059, 2011.
Song, W., Volosin, M., Cragnolini, A.B., Hempstead, B.L., and W.J. Friedman, ProNGF induces PTEN via p75NTR to suppress Trk-mediated survival signaling in brain neurons, J Neurosci. 30(46):15608-15615, 2010.
W.J. Friedman, Proneurotrophins, seizures, and neuronal apoptosis, Neuroscientist 16(3): 244-252, 2010.
Vilar, M., Charalampopoulos, I., Kenchappa, R.S., Reversi, A., Klos-Applequist, J.M., Karaca, E., Simi, A., Spuch, C., Choi, S., Friedman, W.J., Ericson, J., Schiavo, G., Carter, B.D., and C.F. Ibáñez, Ligand-independent signaling by disulfide-crosslinked dimers of the p75 neurotrophin receptor, J Cell Sci 122(Pt18): 3351-3357, 2009.
Choi, S., and W.J. Friedman, Inflammatory cytokines IL-1β and TNF-α regulate p75NTR expression in CNS neurons and astrocytes by distinct cell-type-specific signalling mechanisms, ASN Neuro 1(2), 2009.
Smith, D.E., Lipsky, B.P., Russell, C., Ketchem, R.R., Kirchner, J., Hensley, K., Huang, Y., Friedman, W.J., Boissonneault, V., Plante, M.M., Rivest, S., and J.E. Sims, A central nervous system-restricted isoform of the interleukin-1 receptor accessory protein modulates neuronal responses to interleukin-1, Immunity 30(6): 817-831, 2009.
Vilar, M., Charalampopoulos, I., Kenchappa, R.S., Simi, A., Karaca, E., Reversi, A., Choi, S., Bothwell, M., Mingarro, I., Friedman, W.J., Schiavo, G., Bastiaens, P.I., Verveer, P.J., Carter, B.D., and C.F. Ibáñez, Activation of the p75 neurotrophin receptor through conformational rearrangement of disulphide-linked receptor dimers, Neuron 62(1):72-83, 2009.
Cragnolini, A., Y. Huang, P. Gokina and W.J. Friedman, NGF inhibits proliferation of astrocytes via the p75 Neurotrophin Receptor, Glia, 57(13): 1386-1392, 2009.
Volosin, M., C. Trotter, A. Cragnolini, R. Kenchappa, B.L.Hempstead, B.D.Carter, and W.J. Friedman, Induction of proneurotrophins and activation of p75NTR-mediated apoptosis via NGF Receptor Interacting Factor (NRIF) in hippocampal neurons after seizures, J. Neurosci. 28 (39): 9870-9879, 2008.
Cragnolini, A., and W.J. Friedman, The function of p75NTR in Glia, Trends in Neurosciences 31 (2): 99-104, 2008.
Volosin, M., W. Song, R. D. Almeida, B.L. Hempstead, and W.J. Friedman, Interaction of survival and death signaling in basal forebrain neurons: Roles of neurotrophins and proneurotrophins, J. Neurosci, 26 (29):7756-7766, 2006.
Friedman, W.J., Interactions of interleukin-1 with neurotrophic factors in the CNS: Beneficial or Detrimental? Mol. Neurobiol., 32 (2): 133-144, 2005.
Srinivasan, D., J.-H. Yen, D.J. Joseph, and W.J. Friedman, Cell type specific interleukin-1B signaling in the central nervous system, J. Neurosci., 24 (29): 6482-6488, 2004.
Troy, C.M., J.E. Friedman, and W.J. Friedman, Mechanisms of p75-mediated death of hippocampal neurons: Role of caspases, J. Biol. Chem., 277 (37): 34295-34302, 2002.
Friedman, W.J. Cytokines regulate expression of the type 1 interleukin-1 receptor in rat hippocampal neurons and glia. Exp. Neurol. 168: 23-31, 2001.
Friedman, W.J., Neurotrophins induce death of hippocampal neurons via the p75 receptor, J. Neurosci., 20 (17): 6340-6346, 2000.
Friedman, W.J. and L.A. Greene, Neurotrophin signaling via Trks and p75, Experimental Cell Research, 253:131-142, 1999.