A significant subpopulations of nociceptive sensory neurons (IB4/Ret neurons) has been recently found to switch their neurotrophins requirements from nerve growth factor (NGF) to glial cell line-derived neurotrophic factor (GDNF). IB4/Ret neurons are quite sensitive to trophic deprivation caused by injury. GDNF administration appears to reverse the deficits in these neurons. This proposal will test the hypotheses that IB4/Ret neurons are vulnerable to diabetic neuropathy and they respond differently to injury than other populations in diabetes. This information may reveal that these cells are sensitive to therapeutic actions of GDNF, and not NGF.
The specific aims are to determine the sensitivity of IB4/Ret neurons to diabetes by measuring changes in selective markers expressed by IB4/Ret neuron in streptozotocin (STZ)-induced mice. The study will characterize differences between NGF-responsive (trkA) and IB4/Ret neurons in their capacity to express genes that are required for regeneration but are suppressed in diabetes. Changes in gene expression for GAP-43 and Ta1 a-tubulin will be compared between TrkA and IB4/Ret populations in axotomized, STZ-induced mice. The ability of GDNF or NGF to enhance expression of these genes in IB4/Ret neurons will be tested by supplying trophins to axotomized, STZ-induced mice. The long-term goal of this project is to analyze the responses of sensory neurons to experimental diabetes and couple these results with new information about the trophic needs of affected neurons to design treatments with better specificity for DN. Results from this study will provide specific evidence tha sensory neurons have varied susceptibilities to diabetes related to their functions and neurotrophic responsiveness, and suggest GDNF as a candidate to be used in treatments for diabetic neuropathy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS038844-02
Application #
2892481
Study Section
Special Emphasis Panel (ZRG2-NMS (02))
Program Officer
Nichols, Paul L
Project Start
1998-09-30
Project End
2001-08-31
Budget Start
1999-09-01
Budget End
2001-08-31
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Kansas
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
016060860
City
Kansas City
State
KS
Country
United States
Zip Code
66160
Gandhi, Rohan; Ryals, Janelle M; Wright, Douglas E (2004) Neurotrophin-3 reverses chronic mechanical hyperalgesia induced by intramuscular acid injection. J Neurosci 24:9405-13
Christianson, Julie A; Ryals, Janelle M; McCarson, Kenneth E et al. (2003) Beneficial actions of neurotrophin treatment on diabetes-induced hypoalgesia in mice. J Pain 4:493-504
Christianson, Julie A; Riekhof, John T; Wright, Douglas E (2003) Restorative effects of neurotrophin treatment on diabetes-induced cutaneous axon loss in mice. Exp Neurol 179:188-99
Akkina, S K; Patterson, C L; Wright, D E (2001) GDNF rescues nonpeptidergic unmyelinated primary afferents in streptozotocin-treated diabetic mice. Exp Neurol 167:173-82