Approximately 8% of the U.S. population has type 1 or type 2 diabetes and twice that are prediabetic. Periph-eral neuropathy, an example of a 'dying back neuropathy', is an extremely serious complication found in amajority of diabetics. One such condition, diabetic autonomic neuropathy (DAN), is very common and canlead 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, knowl-edge that is vital for preventing, and possibly reversing, this neuropathy. Diabetic neurons exhibit deficits innerve regeneration. Many researchers postulate that this is an underlying factor in the etiology of neuropathyand that normal regeneration, if it could be restored, could compensate for on-going axonal degeneration re-sulting from hyperglycemia. Much is now known about signals promoting regeneration in normal animals, butthese advances have not been applied to studying the deficits in diabetes. Our laboratory has studied the re-sponses of normal sympathetic neurons to injury for the past twenty years. Focusing on changes in regenera-tion-associated gene expression and the increased growth capacity after injury, we discovered that most ofthese responses depend on injury-induced inflammatory cytokines of the gp130 cytokine family. Theseproteins, well known as immune mediators, are becoming increasingly recognized as serving also as injurysignals within the nervous system. For example, we demonstrated an obligatory role of these cytokines in spe-cific changes in gene expression and in the intrinsic growth capacity of normal sympathetic neurons after in-jury. We propose to adapt the methods we have used and the lessons we have learned in normal animals toexamine the cause(s) and potential treatment(s) for DAN in an in vivo and an in vitro mouse model system ofdiabetes. The central hypothesis of this proposal is as follows: Sympathetic complications of diabetes result inpart from decreased gp130 cytokine signaling due to a decrease in cytokine induction in non-neuronal cellsand/or a decrease in cytokine responsiveness by injured neurons. These changes lead to a decrease in rege-neration-associated gene expression, decreased neurite outgrowth, decreased regeneration and decreasedrecovery of end organ function, deficits that might be reversed by cytokine replacement therapy. Using thesemouse models, we propose to examine the regulation of cytokine expression and responsiveness, the ability ofa conditioning lesion to increase the growth capacity of sympathetic neurons, and the expression of selectedgenes known to be important for nerve regeneration, and we will determine if any defects can be improved byadministering cytokines. In addition, we will use the sympathetic innervation of sweat glands to look at regen-eration in vivo and return of autonomic function in diabetes. We expect these studies on gp130 cytokines willhelp to elucidate an underlying cause for diabetic neuropathy and hopefully lead to treatments--such as cyto-kine 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 diabetics and how this may result from deficits in signaling by a family of inflammatory molecules that we have identified as playing 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)
High Priority, Short Term Project Award (R56)
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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
Schools of Medicine
United States
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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
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
Zigmond, Richard E (2012) Cytokines that promote nerve regeneration. Exp Neurol 238:101-6