Abstract

The function of the nervous system depends upon specific neural connections. Our research is focused on factors from peripheral target tissues like skin that govern the development and maintenance of the sensory nervous system. While target tissues have well-known effects on neuronal survival, this proposal focuses on additional differentiative actions by skin factors. This proposal is based on our discovery that activin, a member of the Transforming Growth Factor beta superfamily, is a potent differentiative factor for sensory neurons that increases neuropeptides responsible for pain perception and inflammation. We propose that during development and following adult skin wounds, activin derived from skin acts on cutaneous neurons to increase sensory neuropeptides essential for pain sensation and vasodilatory events essential for wound healing. To test this hypothesis, we will define how the activin signal initiated at nerve terminals in skin is conveyed to the sensory neuronal cell body to identify potential molecular targets for therapeutic intervention in pain management. Not all sensory neurons respond to activin, and activation-specific antibodies will be used to identify the pool of responsive neurons. Reduction of intracellular smad signaling will be used to test if these signals are essential for activin's biological effects. Additional characteristics of embryonic and adult neurons altered by activin will be identified. The biochemical and physiological consequences of activin induction of neuropeptides will be tested by modulating activin to alter neuropeptides and pain sensation following injury. The overall aim of this grant its to understand the mechanism by which activin and activin regulated signaling pathways exert their effects on the development and plasticity of the nervous system. This project will provide important information on the role of target-derived activin in the coordinated physiological response to neural injury. These studies will provide a molecular basis for intervention in inflammatory pain syndromes and may offer new diagnostic and therapeutic tools in clinical medicine. ? ?

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS039316-06
Application #
6858692
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Porter, Linda L
Project Start
1999-12-01
Project End
2008-01-31
Budget Start
2005-02-01
Budget End
2006-01-31
Support Year
6
Fiscal Year
2005
Total Cost
$318,431
Indirect Cost

  Institution

Name
Case Western Reserve University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106

  Publications

Mukerji, Shibani S; Rainey, Riley N; Rhodes, Jamie L et al. (2009) Delayed activin A administration attenuates tissue death after transient focal cerebral ischemia and is associated with decreased stress-responsive kinase activation. J Neurochem 111:1138-48
Zhu, Weiguo; Xu, Pin; Cuascut, Fernando X et al. (2007) Activin acutely sensitizes dorsal root ganglion neurons and induces hyperalgesia via PKC-mediated potentiation of transient receptor potential vanilloid I. J Neurosci 27:13770-80
Xu, P; Hall, A K (2007) Activin acts with nerve growth factor to regulate calcitonin gene-related peptide mRNA in sensory neurons. Neuroscience 150:665-74
Mukerji, Shibani S; Katsman, Ekaterina A; Wilber, Charles et al. (2007) Activin is a neuronal survival factor that is rapidly increased after transient cerebral ischemia and hypoxia in mice. J Cereb Blood Flow Metab 27:1161-72
Berti-Mattera, Liliana N; Gariepy, Cheryl E; Burke, Rebecca M et al. (2006) Reduced expression of endothelin B receptors and mechanical hyperalgesia in experimental chronic diabetes. Exp Neurol 201:399-406
Xu, Pin; Van Slambrouck, Charles; Berti-Mattera, Liliana et al. (2005) Activin induces tactile allodynia and increases calcitonin gene-related peptide after peripheral inflammation. J Neurosci 25:9227-35
Cruise, Bethany A; Xu, Pin; Hall, Alison K (2004) Wounds increase activin in skin and a vasoactive neuropeptide in sensory ganglia. Dev Biol 271:1-10
Miller, Robert H; Dinsio, Kyl; Wang, Rae et al. (2004) Patterning of spinal cord oligodendrocyte development by dorsally derived BMP4. J Neurosci Res 76:9-19
Angley, Catherine; Kumar, Mallika; Dinsio, Kyl J et al. (2003) Signaling by bone morphogenetic proteins and Smad1 modulates the postnatal differentiation of cerebellar cells. J Neurosci 23:260-8
Hall, Alison K; Burke, Rebecca M; Anand, Malini et al. (2002) Activin and bone morphogenetic proteins are present in perinatal sensory neuron target tissues that induce neuropeptides. J Neurobiol 52:52-60

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