Abstract

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG008938-13
Application #
2457531
Study Section
Neuroscience, Behavior and Sociology of Aging Review Committee (NBSA)
Program Officer
Finkelstein, David B
Project Start
1990-01-01
Project End
1999-07-31
Budget Start
1997-08-01
Budget End
1999-07-31
Support Year
13
Fiscal Year
1997
Total Cost
Indirect Cost

  Institution

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

  Publications

Kleschevnikov, Alexander M; Belichenko, Pavel V; Faizi, Mehrdad et al. (2012) Deficits in cognition and synaptic plasticity in a mouse model of Down syndrome ameliorated by GABAB receptor antagonists. J Neurosci 32:9217-27
Zhao, Yunfeng; Chaiswing, Luksana; Bakthavatchalu, Vasudevan et al. (2006) Ras mutation promotes p53 activation and apoptosis of skin keratinocytes. Carcinogenesis 27:1692-8
Mansouri, Abdellah; Muller, Florian L; Liu, Yuhong et al. (2006) Alterations in mitochondrial function, hydrogen peroxide release and oxidative damage in mouse hind-limb skeletal muscle during aging. Mech Ageing Dev 127:298-306
Zhao, Yunfent; Oberley, Terry D; Chaiswing, Luksana et al. (2002) Manganese superoxide dismutase deficiency enhances cell turnover via tumor promoter-induced alterations in AP-1 and p53-mediated pathways in a skin cancer model. Oncogene 21:3836-46
Huang, T T; Carlson, E J; Gillespie, A M et al. (2000) Ubiquitous overexpression of CuZn superoxide dismutase does not extend life span in mice. J Gerontol A Biol Sci Med Sci 55:B5-9
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
Akgur, F M; Brown, M F; Zibari, G B et al. (2000) Role of superoxide in hemorrhagic shock-induced P-selectin expression. Am J Physiol Heart Circ Physiol 279:H791-7
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

Showing the most recent 10 out of 102 publications