Peter J. Dyck, MD - US grants

This renewal program project grant seeks continued support for an integrated program of research aimed at understanding the cellular and molecular mechanisms involved in nerve fiber degeneration and regeneration in models of human neuropathy and in human neuropathy itself. A major focus is the study of diabetic neuropathy. The primary objective of Project 36 is: 1) to determine the staged prevalence of the major types of diabetic neuropathy in Rochester, MN; 2) to develop and validate meaningful measures of neuropathy and approaches to stage severity; and 3) to longitudinally assess occurrence of neuropathy over time, to ascertain changes in neuropathy over time and the risk factor with changes in neuropathy with time. Healthy subjects, randomly selected from the same population, are evaluated for the occurrence of neuropathy (to estimate frequency of neuropathy in controls). These subjects are re-evaluated 4 years later to determine change of neuropathic evaluation results with age. In Project 37 experimental and human nerve tissue is evaluated to: compare clinical to neuropathologic criteria for neuropathy, to assess the influence of metabolic derangements, and to assess for specific neuropathologic explanations for neuropathy. This human and experimental tissue is also studied to assess the hypothesis that microvessel complications are implicated in diabetic neuropathy. In Project 31 a repertoire of physiologic and biochemical techniques are used to assess for nerve ischemia in models of experimental diabetes. The studies will be extended to the cell body, and, based on insights gained from recent studies, will undertake 3 studies with treatment implications for human diabetic neuropathy. In Project 38, Poduslo and coworkers systematically explore the effect of glycation of sugars on their transfer characteristics across perineurial and endoneurial barriers. Does the increase transfer lead to accumulation of these glycated proteins and is it deleterious? Also assessed is whether glycation of protein might be exploited as a method of transferring needed metabolites or medication into nerve. In Project 39, Windebank studies experimental models of neuropathy (especially cisplatinum) as a realistic model of nerve fiber degeneration and regeneration and the influence of growth factors in development, regeneration, and prevention of nerve injury.

This renewal program project grant seeks continued support for an integrated program of research aimed at understanding the cellular and molecular mechanisms involved in nerve fiber degeneration and regeneration in models of human neuropathy and in human neuropathy itself. A major focus is the study of diabetic neuropathy. The primary objective of Project 36 is: 1) to determine the staged prevalence of the major types of diabetic neuropathy in Rochester, MN; 2) to develop and validate meaningful measures of neuropathy and approaches to stage severity; and 3) to longitudinally assess occurrence of neuropathy over time, to ascertain changes in neuropathy over time and the risk factor with changes in neuropathy with time. Healthy subjects, randomly selected from the same population, are evaluated for the occurrence of neuropathy (to estimate frequency of neuropathy in controls). These subjects are re-evaluated 4 years later to determine change of neuropathic evaluation results with age. In Project 37 experimental and human nerve tissue is evaluated to: compare clinical to neuropathologic criteria for neuropathy, to assess the influence of metabolic derangements, and to assess for specific neuropathologic explanations for neuropathy. This human and experimental tissue is also studied to assess the hypothesis that microvessel complications are implicated in diabetic neuropathy. In Project 31 a repertoire of physiologic and biochemical techniques are used to assess for nerve ischemia in models of experimental diabetes. The studies will be extended to the cell body, and, based on insights gained from recent studies, will undertake 3 studies with treatment implications for human diabetic neuropathy. In Project 38, Poduslo and coworkers systematically explore the effect of glycation of sugars on their transfer characteristics across perineurial and endoneurial barriers. Does the increase transfer lead to accumulation of these glycated proteins and is it deleterious? Also assessed is whether glycation of protein might be exploited as a method of transferring needed metabolites or medication into nerve. In Project 39, Windebank studies experimental models of neuropathy (especially cisplatinum) as a realistic model of nerve fiber degeneration and regeneration and the influence of growth factors in development, regeneration, and prevention of nerve injury.

DESCRIPTION: This is a request for five years of support of a study of diabetic neuropathy, a common complication of a common disease. The work is a continuation and extension of work originally performed as part of a clinical research center grant. It is an ongoing large-scale cross-sectional and longitudinal clinical and epidemiological study of nerve, eye, kidney, and large artery complications in diabetes mellitus in Rochester, MN (patients of primarily Northern European extraction) and in Prairie Island, MN (Mdewakanton Dakota native people). The main objectives are to delineate the frequency, rate of progression, health, work and life outcomes, and predictive risk profiles in various diabetic neuropathies. Major efforts during previous funding periods were directed towards developing diagnostic criteria and quantitative methods for objectively scoring the severity of peripheral nerve disease. Those tools are now available and will be used in the proposed studies. There are four specific aims. The first is to develop and evaluate clinical end points and composite scores for assessing diabetic polyneuropathy, proximal diabetic neuropathy, diabetic truncal radiculopathy, and upper limb mononeuropathies. Normative scales will be developed and changes in these scores with time will be assessed in the different groups of diabetics. The second aim is to evaluate the incidence, prevalence, and clinical outcomes associated with specific manifestations of diabetic neuropathy in the cohorts of diabetics maintained by the Mayo Clinic and extend these observations to include a Native American population. Risk profiles will be developed. The third aim is to identify risk factors for the various neuropathies and examine whether there are identifiable groups of diabetics who are at elevated risk of peripheral nerve complications. The fourth aim is to use the above information to test the following hypotheses: that the various forms of diabetic neuropathy have different pathogenic mechanisms; that in diabetic polyneuropathy hyperglycemia either directly damages Schwann cells or axons or first damages endoneurial microvessels (probably by mechanisms involving altered blood flow and hypoxia); that immune mechanisms are involved in the development of proximal diabetic neuropathy, truncal radiculopathy, and oculomotor neuropathy.