1985 — 2010 |
Schmidt, Robert E [⬀] Schmidt, Robert E [⬀] Schmidt, Robert E [⬀] |
K04Activity Code Description: Undocumented code - click on the grant title for more information. R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. R37Activity Code Description: To provide long-term grant support to investigators whose research competence and productivity are distinctly superior and who are highly likely to continue to perform in an outstanding manner. Investigators may not apply for a MERIT award. Program staff and/or members of the cognizant National Advisory Council/Board will identify candidates for the MERIT award during the course of review of competing research grant applications prepared and submitted in accordance with regular PHS requirements. |
Experimental Diabetic Autonomic Neuropathy
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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1992 — 2006 |
Schmidt, Robert Edward [⬀] Schmidt, Robert Edward [⬀] Schmidt, Robert Edward [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Neuropathology of the Aging Sympathetic Nervous System
Autonomic dysfunction is an increasingly recognized problem in aging humans. We have demonstrated that aging in both the human and rodent sympathetic nervous system is characterized by the reproducible development of distinctive, markedly enlarged, terminal axons and synapses with the histopathologic appearance of neuroaxonal dystrophy (NAD). We have made several recent discoveries which represent significant advances in understanding the pathogenesis of age-related autonomic dysfunction and now propose a focused analysis of synapse- associated events that may underlie human disease. We have found that short courses of IGF-I or NT-3 result in significant reduction in established sympathetic NAD in aged rats. Contrary to conventional thinking, age-related sympathetic NAD is not a simple NGF deficiency disease and, surprisingly, exogenously administered NGF may actually worsen NAD. Since our last submission, we have discovered that suicidal ingestion of paraquat (PQ), a superoxide-generating herbicide, results in autonomic failure and the development of NAD in human sympathetic ganglia, identical in structure and immunoprofile to that found in aging. We have found that PQ also produces dystrophic axons in cultures of rat sympathetic neurons, which promises to provide mechanistic insights into the proposed oxidative pathogenesis of age-related sympathetic NAD. Based on our studies, we propose that NAD is a distinctive neuropathological end-point whose formation critically interferes with synaptic transmission and results from a combination of oxidative nerve terminal injury and defective synaptic adaptation. We propose in the current research plan to test the following hypotheses: 1) that oxidative stress causes nerve terminal injury and is the initiating stimulus in the development of age-related NAD; 2) that NAD reflects an age-related defect in synaptic plasticity, collateral axonal sprouting and/or regeneration; 3) that this defect is, at least in part, secondary to an age-related excess of NGF and diminished IGF-1 and NT-3; and, 4) that NAD formation leads to defective interneuronal signal transmission and endorgan dysfunction. The results of these experiments should provide insight not only into autonomic dysfunction, but into a variety of pathologic processes in which NAD is a prominent component.
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2006 — 2007 |
Schmidt, Robert Edward [⬀] Schmidt, Robert Edward [⬀] Schmidt, Robert Edward [⬀] |
P41Activity Code Description: Undocumented code - click on the grant title for more information. |
A Potent Sorbitol Dehydrogenase Inhibitor Exacerbates Sympathetic Autonomic |
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2011 |
Schmidt, Robert Edward [⬀] Schmidt, Robert Edward [⬀] Schmidt, Robert Edward [⬀] |
S10Activity Code Description: To make available to institutions with a high concentration of NIH extramural research awards, research instruments which will be used on a shared basis. |
Transmission Electron Microscope
DESCRIPTION (provided by applicant): Funds are requested for the purchase of a new transmission electron microscope (TEM) to support NIH- funded research at Washington University Medical School (WUMS). This proposal will support 40+ NIH grant projects of 6 Major Users and 12 Minor Users, all with substantial, previously published EM experience and demonstrable ongoing need for electron microscopy. Planned EM applications include ultrastructural imaging of subcellular pathology involving multiple organ systems and disease models. This acquisition will contribute to the capability of the EM facility for day to day research TEM and to advance the research capability of a growing group of our investigators and will undoubtedly also serve the needs of new investigators recruited during the microscope's lifetime. Specifically, we intend to replace our 20+ year old JEOL 1200 TEM which is rapidly aging and reaching the end of its dependable lifespan with a new generation 120 kV TEM, the JEOL 1400. Not only will this microscope perform all of the tasks our current microscope handles more efficiently and dependably, but its improved capabilities will extend our research in ways not previously possible. Over the last few years investigators at WUMS have sought out our Research Electron Microscopy Facility (directed by Dr. Schmidt, the PI of this shared instrumentation grant) as an important tool in the advance of a variety of biologic problems. By far our most substantial and continuing use has involved 6 major user groups who have used TEM as an essential tool in their research programs and 12 minor users whose use has been more occasional but no less critical to resolving individual experimental issues. Our microscope has been available to WUMS investigators irrespective of department affiliation on a fee-for-service basis and at a subsidized rate to members of our Diabetes Research Training Center which contributes to its upkeep. Installation of the requested microscope within this established EM Facility will assist in user training, protocol development, scheduling and billing under the supervision of a highly experienced technical staff and Director who together will train and assist users. We have seen a burgeoning interest in the use of EM by graduate students and postdoctoral fellows (see Table C3) who have recognized the insight ultrastructure adds to their research. A new microscope will permit the analysis of mitochondria, axons and nerve terminals, myelin structure, and will contribute to the examination of pancreatic dendritic cell and osteoclast function. No other electron microscope at Washington University has the capability to substitute for the microscope we request, either because of its age or oversubscription which limits our ability to perform world-class research. PUBLIC HEALTH RELEVANCE: The rapidly approaching obsolescence of our JEOL 1200 transmission electron microscope resulting in delays in providing ultrastructural analysis to our large user group has interfered with the ability of investigators at Washington University School of Medicine to perform world-class science and slows the analysis of neurodegenerative, cardiac, gastrointestinal, metabolic and bone diseases. There is no doubt that basic scientific discoveries supported by a new generation electron microscope with enhanced capability and dependability will contribute to the understanding of some of the most prevalent scourges of human health and expedite the development and application of novel therapies.
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