gp130 Cytokines, Diabetic Autonomic Neuropathy, and Nerve Regeneration

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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 a majority of diabetics. One such condition, diabetic autonomic neuropathy (DAN), is very 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, knowl- edge that is vital for preventing, and possibly reversing, this neuropathy. Diabetic neurons exhibit deficits in nerve regeneration. Many researchers postulate that this is an underlying factor in the etiology of neuropathy and 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, but these 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 of these responses depend on injury-induced inflammatory cytokines of the gp130 cytokine family. These proteins, well known as immune mediators, are becoming increasingly recognized as serving also as injury signals 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 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 non-neuronal cells and/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 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 responsiveness, the ability of a conditioning lesion to increase the growth capacity of sympathetic neurons, and the expression of selected genes known to be important for nerve regeneration, and we will determine if any defects can be improved by administering 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 will help 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.