Willis, Dianna , PhD
Altered axonal mRNA transport in diabetic peripheral neuropathy
General Research Subject: Type 1 Diabetes
Type of Grant: Basic Science
Project Start Date: January 1, 2012
Project End Date: December 31, 2014
Funded By the Order of the Amaranth Diabetes Foundation
Nearly two-thirds of individuals with diabetes will eventually suffer from nerve degeneration. Sensation, such as pain and temperature, is most often the first affected. Diabetic peripheral neuropathy, which primarily affects the hands and feet, can be quite severe. There are no effective treatments for nerve degeneration in diabetes and the cause of this disorder remains unknown. Nerve degeneration in diabetes is likely to be caused by the combined and cumulative effects of many insults, resulting in decreased health of the sensory nervous system. This decreased health of the nervous system likely makes it more sensitive to injury. Re-growth of injured sensory nerves is delayed in diabetic animals and this failure to regenerate leads to even further nervous system dysfunction. The goal of this proposal is to understand the mechanisms that contribute to this delayed regeneration by focusing on the contribution of proteins that are locally made within the distant processes of the neuron. These proteins play a critical role in successful regeneration. Failure of diabetic neurons to properly transport the mRNA templates for these proteins into the axons and then subsequently generate these proteins locally may account for their impaired regeneration capacity. Understanding the mechanisms of delayed nerve regeneration may point to additional therapies for diabetic peripheral neuropathy.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
Up to two-thirds of individuals that suffer from diabetes mellitus will eventually develop peripheral neuropathy. The cause of this often debilitating complication of diabetes remains unknown and there are currently no effective treatments. The sensory nervous system, in particular pain and temperature, is most often the first affected in diabetic peripheral neuropathy. Regeneration of damaged peripheral nerves is delayed in diabetic animals and it is likely that peripheral nerve repair is likewise deficient in humans suffering from diabetes. We hope to understand the mechanisms involved in this axonal regeneration deficit. We hypothesize that the availability of the mRNA templates required for local protein synthesis in axons may be altered in peripheral neurons from diabetic individuals. We hope to identify the individual mRNAs that are altered under diabetic conditions and the mechanism(s) that lead to these alterations. This may provide previously unappreciated avenues for potential therapies to return the axonal environment to normal conditions and prevent or reverse peripheral neuropathy associated with diabetes.
If a person with diabetes were to ask how your project will help them in the future, how would you respond?
As many as two-thirds of individuals with diabetes will eventually suffer from nerve degeneration. There is no effective treatment and the cause remains largely unknown. Nerve degeneration is likely the combined effect of many insults that cumulatively result in decreased health of the sensory nervous system. This likely makes the nervous system more susceptible to trauma - even the minor wear and tear of daily living. The regrowth of damaged processes of sensory neurons (the axons) is limited or delayed in diabetes. We believe that this deficit is caused, at least in part, by alterations in the proteins that are locally made within the axon. Our studies aim to identify if there are differences in the templates used to make these proteins in axons from diabetic neurons compared to normal axons. We also hope to identify the mechanism(s) that lead to these changes. We hope that this knowledge will allow us to develop methods for correcting the levels of proteins locally made within the axons, and that this correction will lead to significant improvement in peripheral neuropathy.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
My family has a history of diabetes and diabetes-related complications, so from a personal standpoint I am hoping to make a contribution to understanding one of the most common and debilitating complications. As medical advances allow for longer and longer lifespans, it is equally critical that the quality of live of these expanded lifespans are maintained. The complications of diabetes severely limit this quality of life. The general interest of our lab, understanding how local protein synthesis in the axon contributes to neuronal health and disease, is a new field of study which may provide significant contribution to the field of diabetic peripheral neuropathy (DPN). DPN is a new avenue of research for my lab and this award will provide much-needed resources to build upon very promising preliminary results.
In what direction do you see the future of diabetes research going?
These studies aim to identify mRNAs that are improperly localized into axons of sensory neurons from diabetic animals. We hope to build upon this information to develop in vivo methods of returning these transcripts to normal axonal levels. Ultimately, we hope to determine if these finding can be replicated in human samples. The availability of human nerve biopsy samples and our method of high-sensitivity in situ hybridization means that we should be able to determine if the same mRNAs show axonal localization deficits in human samples."
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