The long term goals of this program are to elucidate the pathogenesis of the phenotypic abnormalities of Down syndrome (DS) (trisomy 21), with particular emphasis on the relationship between DS and Alzheimer disease, and to assess the role of oxygen free radicals in aging and in neuronal function and survival. Studies of Ts16 brains will be carried out to delineate the mechanisms by which the trisomic state causes dysregulation of neuronal gene expression and affects the structure and survival of basal forebrain cholinergic neurons. The possible role in degenerating Ts16 neurons of neuronal death genes and the regulation of such genes by NGF and other neurotrophins will also be investigated. The effects of various types of exogenous oxidative stress on the function and survival of neurons cultured from Ts16 and CuZn-superoxide dismutase (SOD) transgenic mouse brains, both of which have elevated CuZnSOD activities, will be studied, as will the roles of NMDA receptors and of nitric oxide and NO synthetase in glutamate-mediated injury of Ts16 and SOD-transgenic neurons. The effects of oxygen free radicals on longevity an on age- related neuronal degeneration and behavioral changes will be investigated in strains of transgenic mice with a wide range of CuZnSOD activities.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG008938-10
Application #
2050480
Study Section
Neuroscience, Behavior and Sociology of Aging Review Committee (NBSA)
Project Start
1990-01-01
Project End
1998-07-31
Budget Start
1994-08-01
Budget End
1995-07-31
Support Year
10
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Pediatrics
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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Sago, H; Carlson, E J; Smith, D J et al. (2000) Genetic dissection of region associated with behavioral abnormalities in mouse models for Down syndrome. Pediatr Res 48:606-13
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Freeman, B D; Reaume, A G; Swanson, P E et al. (2000) Role of CuZn superoxide dismutase in regulating lymphocyte apoptosis during sepsis. Crit Care Med 28:1701-8
Li, Y; Carlson, E; Murakami, K et al. (1999) Targeted expression of human CuZn superoxide dismutase gene in mouse central nervous system. J Neurosci Methods 89:49-55
Huang, T T; Carlson, E J; Raineri, I et al. (1999) The use of transgenic and mutant mice to study oxygen free radical metabolism. Ann N Y Acad Sci 893:95-112

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