The limited proliferative potential (cellular senescence) of normal human cells in culture has provided an important model for the study of aging at the cellular level. The model has been validated by various data, including the fact that cells from individuals that exhibit premature aging have lower division capability. Evidence that genetic events rather than random damage results in senescence has come from somatic cell hybridization studies which have shown that the senescent phenotype is dominant in hybrids between young and senescent, as well as normal and immortal human cells. In addition, convincing evidence has been obtained to indicate that senescent cells express a surface membrane associated protein inhibitor of initiation of DNA synthesis that is not present in young cells. We hypothesized that expression of this inhibitor is the endpoint of the genetic events resulting in senescence. We have demonstrated by microinjection that DNA synthesis inhibitory mRNA is highly abundant in senescent but not young cells, suggesting the feasibility of cloning the cDNA encoding the inhibitor. We have recently cloned three cDNAs derived from senescent cells by an expression screening approach. These are called sdi or senescent cell derived inhibitors. One clone is expressed at approximately 10 fold higher levels in senescent and quiescent cells compared to cycling young cells. Quiescent cells have been shown to express a protein inhibitor of DNA synthesis with some, but not all, properties of that produced by senescent cells. sdi1 is therefore a good candidate for the gene encoding the protein inhibitor(s) of DNA synthesis. Alternatively, sdi1 could be coding for an inhibitor of DNA synthesis that has not been previously identified as the cDNA sequence has no significant homology to sequences present in GenBank and the EMBL databases. The goals of this proposal are to elucidate the mechanisms of action of sdi1 and to determine its role during in vitro and in vivo aging.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG011066-03
Application #
2052277
Study Section
Molecular Cytology Study Section (CTY)
Project Start
1992-09-30
Project End
1996-07-31
Budget Start
1994-08-01
Budget End
1996-07-31
Support Year
3
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Biochemistry
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
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