Autonomic neuropathy is a significant complication of diabetes resulting in increased patient morbidity and mortality. We have developed and extensively characterized an experimental animal model of diabetic autonomic neuropathy. The regular occurrence of degenerating, regenerating, and pathologically distinctive dystrophic axons has been demonstrated in both noradrenergic axons contained in mesenteric nerves innervating the distal alimentary tract and in preterminal axons and synapses within the prevertebral sympathetic ganglia innervating the bowel of rats with chronic streptozocin (STZ)-induced diabetes. We have systematically investigated the neuropathologic alterations in the prevertebral and paravertebral sympathetic autonomic ganglia of a large series of autopsied diabetic and non-diabetic adult human subjects in which structurally abnormal synapses, i.e., """"""""synaptic dysplasia"""""""", is prominent. We have found close correspondence between the neuropathology of diabetic autonomic neuropathy in the sympathetic nervous system of rodents and man. With the long term goal of understanding the pathogenesis and treatment of diabetic autonomic neuropathy we will take advantage of insights gained from our animal and human studies to: l) test the hypothesis that an apparent defect in axonal regeneration in the diabetic rat sympathetic nervous system may result in the development of neuroaxonal dystrophy (NAD). 2) test the hypothesis that altered levels of NGF or other members of its neurotrophin family may result in the development of NAD in the STZ- diabetic rat. 3) address demonstrated defects in axonal regeneration and possible alterations of neurotrophin content or neuronal response to neurotrophins in vivo by attempting to develop an in vitro model of diabetic autonomic neuropathy using dissociated rat neuronal cell cultures as well as explants of adult chronically diabetic and non-diabetic rat prevertebral and paravertebral sympathetic ganglia. 4) test the hypothesis that altered composition of neurofilaments which accumulate in diabetic human dystrophic nerve terminals in prevenebral sympathetic ganglia or defects in their metabolism by the calpain/calpastatin degradative pathway result in the development of neurofilament laden neuroaxonal dystrophy. 5) test the hypotheses that chronic diabetes alters the three dimensional structure of principal sympathetic neurons and/or diminishes the total number of synapses on principal sympathetic neurons in prevertebral and paravertebral rat sympathetic ganglia. The proposed research plan represents the natural progression of our long term studies of diabetic autonomic neuropathy in human subjects and experimental animal models to directly address its pathogenetic mechanisms and identify potential new therapeutic strategies.
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