The applicants have shown that distinctive markedly enlarged terminal axons and synapses accumulate in the sympathetic nervous systems of aged experimental animals and autopsied humans, and have the pathologic features of neuraxonal dystrophy (NAD). These NAD resemble those that occur in diabetics, have a predilection for superior mesenteric and celiac ganglia, and appear to be selective for some subpopulations of nerve terminals, while completely sparing others. They now wish to test the following hypotheses: 1) that NGF participates in pathogenesis of age-related NAD; and 2) that age-dependent NAD result from abnormal synaptic plasticity, either superimposed on normal synaptic turnover or as a result of injury-induced axonal regeneration and sprouting.
Their specific aims are: 1. To use the aged mouse model and several mutant mouse strains (Wallerian degeneration-delayed (Ola) and senescence accelerated) to determine whether NAD reflect an abnormality of end-organ NGF, are sensitive to exogenous pharmacologic doses of NGF, result in eventual loss of synapses, involve neurons of defined neuropeptide content or targeted endorgans, and interfere with synaptic function. 2. To test whether NAD can be precipitated in vivo by forced regeneration and sprouting of sympathetic neurons or their presynaptic terminals, and whether they develop in a culture system independent of the aged in vivo milieu. 3. To determine whether NAD in aging and diabetic human dorsal root ganglia represents pathologic sprouting of perivascular sympathetic axons and/or dorsal root ganglion neurons.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG010299-09
Application #
6168114
Study Section
Special Emphasis Panel (ZRG1-NLS-3 (01))
Program Officer
Monjan, Andrew A
Project Start
1992-05-01
Project End
2002-04-30
Budget Start
2000-05-01
Budget End
2002-04-30
Support Year
9
Fiscal Year
2000
Total Cost
$282,739
Indirect Cost
Name
Washington University
Department
Pathology
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Schmidt, Robert E; Feng, Dongyan; Wang, Qiuling et al. (2011) Effect of insulin and an erythropoietin-derived peptide (ARA290) on established neuritic dystrophy and neuronopathy in Akita (Ins2 Akita) diabetic mouse sympathetic ganglia. Exp Neurol 232:126-35
Schmidt, Robert E; Green, Karen G; Snipes, Lisa L et al. (2009) Neuritic dystrophy and neuronopathy in Akita (Ins2(Akita)) diabetic mouse sympathetic ganglia. Exp Neurol 216:207-18
Schmidt, Robert E; Parvin, Curtis A; Green, Karen G (2008) Synaptic ultrastructural alterations anticipate the development of neuroaxonal dystrophy in sympathetic ganglia of aged and diabetic mice. J Neuropathol Exp Neurol 67:1166-86
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