• Schmid, Harold H.O. (PI)
  • Schmid, Harold H.O. (PI)
  • Dyck, P. James B (PI)
  • Poduslo, Joseph F (PI)

Project: Research project

Project Details


This renewal program project proposal seeks support for studies
searching for the cellular and molecular mechanisms in models of
human neuropathy and particularily in human diabetic neuropathy
itself. Project 1, is a cross-sectional and longitudinal
epidemiologic study of all insulin-dependent (ID, 80) and a
representative sample of non insulin-dependent (NID, 525)
diabetics in Rochester, MN, designed to provide reliable estimates
of the frequency, severity and outlook of neuropathic, retinal and
renal complications, using validated and often unique tests.
Metabolic derangement and putative risk factors are
prospectively and intensively evaluated so that associations with
end-points of neuropathy can be recognized. Project 2, proposes a
series of neuropathologic studies of nerve tissue obtained at
postmortem, and of sural nerve taken at biopsy, addressing the
fundamental question are pathologic abnormalities of vessels and
ischemia involved in the pathogenesis of diabetic neuropathy.
Which class of vessels, what pathologic alterations, and what
mechanisms are responsible? The association of metabolic
derangement and putative risk factors, as assessed in Projects 1
and 2, and quantitated neuropathologic abnormality, are to be
assessed. An intensive search for microinfarcts is to be
conducted. Arteriole-capillary-venule (ACV) units are to be
reconstructed from serial sections to understand the pattern of
microvascularization in health and diabetic neuropathy. Hypoxia,
arterial ligation, microsphere embolization, nerve degeneration,
lead intoxication and experimental diabetes in rats are used to
induce vessel and nerve fiber alterations with the view to
understanding the relationship between vessel and fiber
abnormality in human neuropathy. Project 3 extends previous
studies of alterations of the nerve microenvironment in
experimental diabetes to chronic autoimmune diabetic neuropathy
and to human diabetic neuropathy. The hierarchy of nerve blood
flow regulation, the mechanisms of capillary closure in hypoxia
and pharmacologic and hyperbaric oxygen approaches to increase
nerve blood flow will be studied. Mathematical modeling and
computer simulation of oxygen delivery and events of energy
metabolism will also be studied. Project 4 focuses on the study of
alteration of the blood-nerve-barrier in experimental and human
neuropathies, emphasizing diabetic neuropathy. Project 5 outlines
studies to isolate and characterize the soluble neuronatrophic
factor produced in response to injury. The studies address which
cells produce the trophic factor, and the biologic role of this
factor in development and regeneration of nerve fibers in health
and disease. Project 6 continues biochemical studies to illucidate
derangements of phospholipid metabolism in peripheral
neuropathy and especially in diabetic neuropathy. Biosynthetic
and degradative enzymes of phospholipid metabolism will be
characterized. The effect of altering inositol phospholipid
metabolism with lithium will also be studied.
Effective start/end date4/1/783/31/98


  • Medicine(all)
  • Neuroscience(all)