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.
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