Over 8% of the U.S. population has type 1 or type 2 diabetes and more than twice that are prediabetic. Peripheral neuropathy, an example of a """"""""dying back neuropathy"""""""", is an extremely serious complication found in a majority of diabetics. One such condition, diabetic autonomic neuropathy (DAN), is common and can lead to a wide range of conditions such as atrial fibrillation, stroke, and sudden unexplained cardiac death, making the development of treatments imperative. The molecular basis of DAN, however, is unknown, know- ledge that is vital for preventing and possibly reversing this neuropathy. Furthermore, most animal studies on diabetes have focused on sensory and motor neurons. Diabetic neurons exhibit deficits in nerve regeneration. Many researchers postulate that this is an underlying factor in the etiology of neuropathy and that normal re- generation, if it could be restored, could compensate for on-going axonal degeneration resulting from hyperglycemia. Much is now known about signals promoting regeneration in normal animals, but these advances have not been applied to studying the deficits in diabetes. Our lab has studied the responses of normal sympathetic neurons to injury for >20 years. Focusing on changes in regeneration-associated gene (RAG) expression and the increased growth capacity after a conditioning lesion, we discovered that many of these responses depend on injury-induced inflammatory cytokines of the gp130 cytokine family. These proteins, well known as immune mediators, are now also recognized as serving as injury signals within the nervous system. For example, we demonstrated an obligatory role of these cytokines in specific changes after injury in gene expression and in the conditioning lesion response of normal sympathetic neurons. We propose to use the lessons we have learned in normal animals to examine the cause(s) and potential treatment(s) for DAN in an in vivo and an in vitro mouse model system of diabetes. The central hypothesis of this proposal is as follows: Sympathetic complications of diabetes result in part from decreased gp130 cytokine signaling due to a decrease in cytokine induction in neurons or non-neuronal cells and/or to a decrease in cytokine responsiveness by injured neurons. These changes lead to a decrease in RAG expression, decreased neurite outgrowth, decreased regeneration and decreased recovery of end organ function, deficits that might be reversed by cytokine replacement therapy. Using these mouse models, we propose to examine the regulation of cytokine expression and responsive- ness in sympathetic ganglia, the expression of selected genes known to be important for nerve regeneration, the extent of regeneration, and the roles of intrinsic and extrinsic factors using nerve grafting techniques, and the extent of the conditioning lesion response. We will then determine if any defects we find can be improved by administering these cytokines. We expect these studies on gp130 cytokines will help to elucidate an under- lying cause for diabetic neuropathy and hopefully lead to treatments--such as cytokine replacement therapy-- that can prevent, lessen, or even reverse this serious complication of diabetes.

Public Health Relevance

Diabetes is a large and growing public health problem in the U.S., and peripheral nerve damage is one of its major complications. Our experiments are designed to examine deficits in nerve regeneration in diabetes and how this may result from deficits in signaling by a family of inflammatory molecules that play an obligatory role in regeneration by normal neurons. We expect our studies will help identify some of the underlying causes of nerve defects in diabetes and ways to protect the neurons and stimulate nerve regeneration.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
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Jones, Teresa L Z
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Case Western Reserve University
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Niemi, Jon P; Filous, Angela R; DeFrancesco, Alicia et al. (2017) Injury-induced gp130 cytokine signaling in peripheral ganglia is reduced in diabetes mellitus. Exp Neurol 296:1-15
Zigmond, Richard E (2017) Heat shock protein that facilitates myelination of regenerating axons. Proc Natl Acad Sci U S A 114:2103-2105
Lindborg, Jane A; Mack, Matthias; Zigmond, Richard E (2017) Neutrophils Are Critical for Myelin Removal in a Peripheral Nerve Injury Model of Wallerian Degeneration. J Neurosci 37:10258-10277
Niemi, Jon P; DeFrancesco-Lisowitz, Alicia; Cregg, Jared M et al. (2016) Overexpression of the monocyte chemokine CCL2 in dorsal root ganglion neurons causes a conditioning-like increase in neurite outgrowth and does so via a STAT3 dependent mechanism. Exp Neurol 275 Pt 1:25-37
DeFrancesco-Lisowitz, A; Lindborg, J A; Niemi, J P et al. (2015) The neuroimmunology of degeneration and regeneration in the peripheral nervous system. Neuroscience 302:174-203
Cohen, Matthew R; Johnson, William M; Pilat, Jennifer M et al. (2015) Nerve Growth Factor Regulates Transient Receptor Potential Vanilloid 2 via Extracellular Signal-Regulated Kinase Signaling To Enhance Neurite Outgrowth in Developing Neurons. Mol Cell Biol 35:4238-52
Niemi, Jon P; DeFrancesco-Lisowitz, Alicia; Roldán-Hernández, Lilinete et al. (2013) A critical role for macrophages near axotomized neuronal cell bodies in stimulating nerve regeneration. J Neurosci 33:16236-48