Aging and diabetes are associated with increased generation and deposition of Advanced Glycation Endproducts, or AGEs, the products of nonenzymatic glycation/oxidation of proteins/lipids. As human subjects age, the incidence of insulin resistance and, often, frank hyperglycemia rises. Long-lived proteins of the peripheral nervous system (PNS) are highly susceptible to AGE modification. AGEs, an heterogeneous class of molecules, may modify cellular function by an array of distinct mechanisms. One such mechanism is by their ligation of the signal transduction receptor, RAGE. RAGE also interacts with S100/calgranulins and amphoterin (or high mobility box group 1, HGMB1), which display diverse functions, such as neurite outgrowth and inflammation. Among the complications of diabetes, symmetrical neuropathy of the sensory and autonomic nervous systems affects significant numbers of diabetic subjects. Evidence accrued from the first five years of this Project has suggested an innate, survival role for RAGE in response to acute peripheral nerve injury. In euglycemia, transient and sharply-limited upregulation of RAGE (particularly in mononuclear phagocytes [MP] and neuronal/axonal structures) and its ligands is linked to RAGE-dependent inflammation and neurite outgrowth that contribute beneficially to regeneration. In diabetes, regeneration consequent to acute injury, such as crush, is significantly impaired. We hypothesize that in diabetes, chronic and sustained accumulation of AGEs and RAGE ligands, and upregulation of RAGE, perturbs homeostatic mechanisms in the peripheral nerve, leading to chronic dysfunction. Upon superimposed acute nerve injury, RAGE-dependent mechanisms sustain inflammation and neuronal dysfunction, and thwart regeneration. This proposal will address the fundamental question of whether RAGE/RAGE signaling globally, or specifically in cells of MP lineage or neurons, is protective or destructive to peripheral neurons in diabetes. We propose that in euglycemia, acute engagement of RAGE/RAGE signaling in both cell types is protective for peripheral neurons, but that chronic activation in diabetes promotes long-term neuronal dysfunction in the absence or presence of superimposed acute injury. This Project is critically linked to Project 1, as studies in chronic AB-enrichment in the CMSstrongly support deleterious and maladaptive roles for RAGE in neuronal stress. As antagonism of RAGE nears clinical trials in Alzheimer's Disease and diabetes, it is imperative to dissect the beneficial vs maladaptive impact of RAGE in both the CMS and PNS, and in chronic stress vs acute injury. Projects 1 and 2 are uniquely positioned to address these questions due to the long-time collaboration of the leaders of these Projects. Project 2 will employ Cores A and B through all five years of this Program.
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