The long-range goal of this research is to understand the molecular mechanisms of how axonal injury in the peripheral nervous system induces Schwann cells to form a micro-environment supportive of axonal regeneration. A key event in this process is the dedifferentiation and proliferation of the mitotically quiescent Schwann cells of adult peripheral nerve. Although the identity of the molecular signal(s) triggering the Schwann cell response to axonal injury is unknown, members of the neuregulin (NRG) family of growth and differentiation factors are likely candidates as these molecules are potent Schwann cell mitogens and differentiation factors in vitro. Based on our preliminary data, we hypothesize that NRGs, initially released from the injured axon and subsequently produced by the Schwann cells and macrophages, critically regulate axonal regeneration via induction of Schwann cell proliferation. To test our hypothesis, we propose an integrated approach in which recombinant NRG proteins and specific NRG inhibitors developed in our laboratory will be used to establish whether alpha- and/or beta-NRGs are both necessary and sufficient for postaxotomy Schwann cell proliferation in vivo. We will determine: 1) whether soluble, biologically active forms of the predominant beta- and alpha-NRGs expressed in axotomized nerve are sufficient for Schwann cell dedifferentiation and proliferation in vivo; 2) whether NRGs are necessary for postaxotomy Schwann cell dedifferentiation and proliferation; and 3) whether NRGs activate specific intracellular signaling pathways mediating Schwann cell proliferation and whether beta- and alpha-NRGs differ in their ability to activate these pro-proliferative signaling pathways. The proposed research plan represents a natural progression of our work to date and will provide valuable insights into the molecular mechanisms underlying axonal regeneration in traumatic nerve injury and primary axonopathies as well as having important implications for nervous system neoplasia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS037514-04
Application #
6539981
Study Section
Special Emphasis Panel (ZRG1-MDCN-7 (01))
Program Officer
Kleitman, Naomi
Project Start
1999-07-30
Project End
2003-04-30
Budget Start
2002-05-01
Budget End
2003-04-30
Support Year
4
Fiscal Year
2002
Total Cost
$231,391
Indirect Cost
Name
University of Alabama Birmingham
Department
Pathology
Type
Schools of Medicine
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Ricart, Karina; J Pearson Jr, Richard; Viera, Liliana et al. (2006) Interactions between beta-neuregulin and neurotrophins in motor neuron apoptosis. J Neurochem 97:222-33
Joung, Insil; Harber, Greg; Gerecke, Kimberly M et al. (2005) Improved gene delivery into neuroglial cells using a fiber-modified adenovirus vector. Biochem Biophys Res Commun 328:1182-7
Pearson Jr, Richard J; Carroll, Steven L (2004) ErbB transmembrane tyrosine kinase receptors are expressed by sensory and motor neurons projecting into sciatic nerve. J Histochem Cytochem 52:1299-311
Fallon, Kenneth B; Havlioglu, Necat; Hamilton, Leo H et al. (2004) Constitutive activation of the neuregulin-1/erbB signaling pathway promotes the proliferation of a human peripheral neuroepithelioma cell line. J Neurooncol 66:273-84
Carroll, Steven L; Byer, Stephanie J; Dorsey, Denise A et al. (2004) Ganglion-specific patterns of diabetes-modulated gene expression are established in prevertebral and paravertebral sympathetic ganglia prior to the development of neuroaxonal dystrophy. J Neuropathol Exp Neurol 63:1144-54
Huijbregts, Richard P H; Roth, Kevin A; Schmidt, Robert E et al. (2003) Hypertrophic neuropathies and malignant peripheral nerve sheath tumors in transgenic mice overexpressing glial growth factor beta3 in myelinating Schwann cells. J Neurosci 23:7269-80
Frohnert, Paul W; Stonecypher, Mark S; Carroll, Steven L (2003) Lysophosphatidic acid promotes the proliferation of adult Schwann cells isolated from axotomized sciatic nerve. J Neuropathol Exp Neurol 62:520-9
Frohnert, Paul W; Stonecypher, Mark S; Carroll, Steven L (2003) Constitutive activation of the neuregulin-1/ErbB receptor signaling pathway is essential for the proliferation of a neoplastic Schwann cell line. Glia 43:104-18