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 #
1R01AG013902-01A1
Application #
2001899
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Program Officer
Finkelstein, David B
Project Start
1997-08-15
Project End
2001-07-31
Budget Start
1997-08-15
Budget End
1998-07-31
Support Year
1
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Allegheny University of Health Sciences
Department
Other Health Professions
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19129
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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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Acuna-Castillo, Claudio; Aravena, Mauricio; Leiva-Salcedo, Elias et al. (2005) T-kininogen, a cystatin-like molecule, inhibits ERK-dependent lymphocyte proliferation. Mech Ageing Dev 126:1284-91
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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