The underlying premise of this work is that inhibition of proteolysis observed during aging results in an inhibition of cell proliferation responses, as exemplified by reduced immune function, liver regeneration, and wound-healing. In this proposal, it is hypothesized that inhibition of cysteine proteinases by thiostatin results in impairment in the cell's ability to respond to mitogenic stimuli. To test this, it is proposed to identify: (1) the site(s) within the cell cycle that are affected by thiostatin overexpression, and (2) the molecular mechanisms responsible for inhibition of the MAP kinase pathway of signal transduction in thiostatin-producing cells.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG013902-05
Application #
6168832
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Program Officer
Finkelstein, David B
Project Start
1997-08-15
Project End
2002-02-23
Budget Start
2000-08-15
Budget End
2002-02-23
Support Year
5
Fiscal Year
2000
Total Cost
$172,289
Indirect Cost
Name
Lankenau Institute for Medical Research
Department
Type
DUNS #
125797084
City
Wynnewood
State
PA
Country
United States
Zip Code
19096
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Perez, Viviana; Leiva-Salcedo, Elias; Acuna-Castillo, Claudio et al. (2006) T-kininogen induces endothelial cell proliferation. Mech Ageing Dev 127:282-9
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Perez, Viviana; Velarde, Victoria; Acuna-Castillo, Claudio et al. (2005) Increased kinin levels and decreased responsiveness to kinins during aging. J Gerontol A Biol Sci Med Sci 60:984-90
Aravena, M; Perez, C; Perez, V et al. (2005) T-kininogen can either induce or inhibit proliferation in Balb/c 3T3 fibroblasts, depending on the route of administration. Mech Ageing Dev 126:399-406
Li, Min; Torres, Claudio; Acuna-Castillo, Claudio et al. (2002) Defect in ERK2 and p54(JNK) activation in aging mouse splenocytes. J Gerontol A Biol Sci Med Sci 57:B41-7
Torres, C; Li, M; Walter, R et al. (2001) T-kininogen inhibits fibroblast proliferation in the G(1) phase of the cell cycle. Exp Cell Res 269:171-9
Torres, C; Li, M; Walter, R et al. (2000) Modulation of the ERK pathway of signal transduction by cysteine proteinase inhibitors. J Cell Biochem 80:23-Nov

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