Decreased neurotrophic support has been postulated as a cause of diabetic peripheral neuropathy and exogenous neurotrophic factors have shown some promise for treatment of this diabetic complication. Levels of some neurotrophic factors are decreased in diabetic animals. There is also reason to believe that responsiveness to neurotrophic. factors is altered in diabetes mellitus. The objective of this proposal is to address the role of neurotrophic responsiveness in the pathogenesis of diabetic peripheral neuropathy.
In Specific aim I, we will directly test the intracellular responsiveness of sensory neurons from diabetic rodents to exogenous and endogenous neurotrophins. Application of exogenous NGF and BDNF will show whether the diabetic sensory neurons can initiate appropriate intracellular signaling mechanisms in response to these neurotrophins. Autocrine/paracrine-produced BDNF supports survival of adult sensory neurons in vitro. Curiously, BDNF mRNA is actually increased in sensory ganglia of diabetic animals, raising the question of whether these neurons can respond to BDNF. Responsiveness of these sensory neurons to endogenous BDNF will be determined by selectively inhibiting the BDNF receptor (TrkB) or competitively removing BDNF from the culture medium. The loss of activity of TrkB and downstream signaling pathways (Ras-Erk and P13K-Akt) will provide a measure of the capacity of diabetic sensory neurons to maintain intracellular signaling mechanisms in response to neurotrophins.
In Specific Aim II, we will address the molecular responsiveness of diabetic sensory neurons to the endogenous neurotrophic factors that are increased after nerve injury. Altered neurotrophic factor responsiveness both before and after nerve injury may indeed account for the aborted nerve regeneration seen in diabetic animals. We will use conditioning crush lesions to determine if diabetic sensory neurons can i) generate a population of mRNAs needed for axonal regeneration after nerve injury, and ii) regulate the translation of these mRNAs to rapidly extend axons in vitro.
| Chang, Jay H; Vuppalanchi, Deepika; van Niekerk, Erna et al. (2006) PC12 cells regulate inducible cyclic AMP (cAMP) element repressor expression to differentially control cAMP response element-dependent transcription in response to nerve growth factor and cAMP. J Neurochem 99:1517-30 |
| Chang, Jay H; Mellon, Eric; Schanen, N Carolyn et al. (2003) Persistent TrkA activity is necessary to maintain transcription in neuronally differentiated PC12 cells. J Biol Chem 278:42877-85 |
