The etiology of diabetic peripheral neuropathy (DPN) is complex and involves the degeneration of both neurons and Schwann cells (SCs). Although much attention has focused on how altered growth factor signaling contributes to neuronal dysfunction, a significant gap exists in our understanding of how hyper-glycemia affects gliotrophic factors. Neuregulin-1 (NRG1) is a gliotrophic growth factor that promotes cell survival, mitogenesis and myelination by activating Erb B receptor tyrosine kinases in developing SCs. In contrast, and relevant to the etiology of DPN, pathologic activation of Erb B2 in myelinated SCs can induce demyelination and the onset of peripheral neuropathies. Our broad hypothesis is that diabetes induces an "altered neuregulinism" that contributes to SC degeneration and the progression of DPN. In support of this hypothesis, we provide evidence that diabetes stimulates Erb B2 activity in peripheral nerve and that this correlates with the downregulation of a negative regulator of Erb B2, caveolin-1 (Cav-1). Using myelinated SC/sensory neuron co-cultures, we demonstrate that hyperglycemia decreases Cav-1 levels and enhances NRG1-induced demyelination. Cav-1 may contribute to the degeneration of myelinated axons in vivo as the rate of onset of a mechanical hypoalgesia was faster in diabetic Cav-1 knockout versus wild type mice. Similarly, we show that Erb B2 activity is sufficient to cause a decrease in motor nerve conduction velocity and induce a mechanical hypoalgesia using a novel SC-specific conditional transgenic mouse that upregulates a constitutively-active Erb B2 in response to doxycycline. Thus, our goal is to integrate findings from animal and cellular models to gain mechanistic insight into how pathologic activation of Erb B2 affects SCs and contributes to the onset of sensory dysfunctions in DPN. Our objectives are to: 1) determine the mechanism by which Cav- 1 enhances the degenerative effects of NRG1 under hyperglycemic conditions using myelinated SC/sensory neuron explants from wild type and Cav-1 null mice, 2) determine the necessity/sufficiency of Cav-1 in contributing to Erb B2 activation and the onset of DPN using Cav-1 null mice and 3) determine the effect of diabetes on NRG expression in diabetic nerve and ascertain the sufficiency of Erb B2 in contributing to sensory deficits using novel Erb B2 conditional transgenic mice. This work will provide a new paradigm toward understanding the effect of NRGs in modulating axo-glial interactions in DPN.

Public Health Relevance

Diabetic peripheral neuropathy (DPN) results from the degeneration of nerves that transmit sensations from the legs and arms. Schwann cells (SCs) are specialized cells that closely associate with many nerves and also undergo profound changes in DPN. Our hypothesis is that prolonged hyperglycemic stress alters the response of SCs to growth factors called neuregulins. In adult myelinated nerve, neuregulins can induce demyelination, which contributes to DPN. Using a cell culture model of myelinated nerve, we have identified that glucose increases the degenerative effects of neuregulins. Thus, the objectives of this research are to determine if diabetes affects the expression and activity of neuregulins in diabetic nerve from mice and to identify the molecular events by which neuregulins may induce nerve degeneration. The expected outcome of these studies is that we will identify molecular interactions that may enhance the therapeutic benefit of growth factors in the treatment of DPN.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS054847-04
Application #
7989416
Study Section
Special Emphasis Panel (ZRG1-BDCN-J (03))
Program Officer
Gwinn, Katrina
Project Start
2008-02-01
Project End
2012-11-30
Budget Start
2010-12-01
Budget End
2011-11-30
Support Year
4
Fiscal Year
2011
Total Cost
$307,881
Indirect Cost
Name
University of Kansas Lawrence
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
076248616
City
Lawrence
State
KS
Country
United States
Zip Code
66045
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Ma, Jiacheng; Farmer, Kevin L; Pan, Pan et al. (2014) Heat shock protein 70 is necessary to improve mitochondrial bioenergetics and reverse diabetic sensory neuropathy following KU-32 therapy. J Pharmacol Exp Ther 348:281-92
Pan, Pan; Dobrowsky, Rick T (2013) Differential expression of neuregulin-1 isoforms and downregulation of erbin are associated with Erb B2 receptor activation in diabetic peripheral neuropathy. Acta Neuropathol Commun 1:39
Farmer, Kevin; Williams, S Janette; Novikova, Lesya et al. (2012) KU-32, a novel drug for diabetic neuropathy, is safe for human islets and improves in vitro insulin secretion and viability. Exp Diabetes Res 2012:671673
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Urban, Michael J; Pan, Pan; Farmer, Kevin L et al. (2012) Modulating molecular chaperones improves sensory fiber recovery and mitochondrial function in diabetic peripheral neuropathy. Exp Neurol 235:388-96
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Li, Chengyuan; Ma, Jiacheng; Zhao, Huiping et al. (2012) Induction of heat shock protein 70 (Hsp70) prevents neuregulin-induced demyelination by enhancing the proteasomal clearance of c-Jun. ASN Neuro 4:e00102
Zhang, Liang; Zhao, Huiping; Blagg, Brian S J et al. (2012) C-terminal heat shock protein 90 inhibitor decreases hyperglycemia-induced oxidative stress and improves mitochondrial bioenergetics in sensory neurons. J Proteome Res 11:2581-93
Farmer, Kevin L; Li, Chengyuan; Dobrowsky, Rick T (2012) Diabetic peripheral neuropathy: should a chaperone accompany our therapeutic approach? Pharmacol Rev 64:880-900

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