The ability of a cell to maintain optimum protein synthetic activity impinges upon the ability to divide, to maintain homeostasis and metabolic integrity, and to repair damage. Protein synthetic activity depends, to a substantial extent, upon biosynthesis of ribosomes. A number of observations suggest that ribosome biosynthesis is impaired as a function of age. A series of experiments is proposed to confirm this hypothesis, to elucidate the mechanisms that account for decreased ribosome biosynthetic capacity in aged mice, and to determine the extent to which impairment of this process is related to failure to undergo a mitotic response. Ribosome biosynthetic capacity will be assessed by measurement of expression of component genes including those encoding 45S pre-rRNA (RDNA), 5S RNA, U3 small nuclear RNA (U3nRNA), and ribosomal protein S16 (rpS16). Techniques that are routine in this laboratory will be used to measure transcriptional activity in isolated nuclei, transcription of cloned genes in vitro, and abundance of the products. Experiments will be carried out to test the hypotheses (i) that transcription of these genes is coordinately diminished during aging and (ii) that decreased transcriptional activity is associated with a decrease in the amount or activity of trans-acting factors that are known to regulate the activities of these genes under other circumstances. These studies will be carried out in fractions derived from B lymphocytes of young and aged mice. Parallel studies will be carried out to test the hypothesis that failure B lymphocytes from aged mice to respond to mitotic stimulation relates to defective activation of ribosome biosynthesis (as determined by measurement of expression of the genes listed above).

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
1P01AG010514-01
Application #
3790604
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Type
DUNS #
041367053
City
Galveston
State
TX
Country
United States
Zip Code
77555
Hegde, Muralidhar L; Mantha, Anil K; Hazra, Tapas K et al. (2012) Oxidative genome damage and its repair: implications in aging and neurodegenerative diseases. Mech Ageing Dev 133:157-68
Tann, Anne W; Boldogh, Istvan; Meiss, Gregor et al. (2011) Apoptosis induced by persistent single-strand breaks in mitochondrial genome: critical role of EXOG (5'-EXO/endonuclease) in their repair. J Biol Chem 286:31975-83
Zhang, Haihong; Xie, Chenghui; Spencer, Horace J et al. (2011) Obesity and hepatosteatosis in mice with enhanced oxidative DNA damage processing in mitochondria. Am J Pathol 178:1715-27
Szczesny, Bartosz; Tann, Anne W; Mitra, Sankar (2010) Age- and tissue-specific changes in mitochondrial and nuclear DNA base excision repair activity in mice: Susceptibility of skeletal muscles to oxidative injury. Mech Ageing Dev 131:330-7
Szczesny, Bartosz; Tann, Anne W; Longley, Matthew J et al. (2008) Long patch base excision repair in mammalian mitochondrial genomes. J Biol Chem 283:26349-56
Szczesny, Bartosz; Mitra, Sankar (2005) Effect of aging on intracellular distribution of abasic (AP) endonuclease 1 in the mouse liver. Mech Ageing Dev 126:1071-8
Choksi, K B; Boylston, W H; Rabek, J P et al. (2004) Oxidatively damaged proteins of heart mitochondrial electron transport complexes. Biochim Biophys Acta 1688:95-101
Garg, Nisha; Gerstner, Arpad; Bhatia, Vandanajay et al. (2004) Gene expression analysis in mitochondria from chagasic mice: alterations in specific metabolic pathways. Biochem J 381:743-52
Szczesny, Bartosz; Hazra, Tapas K; Papaconstantinou, John et al. (2003) Age-dependent deficiency in import of mitochondrial DNA glycosylases required for repair of oxidatively damaged bases. Proc Natl Acad Sci U S A 100:10670-5
Bhakat, Kishor K; Izumi, Tadahide; Yang, Suk-Hoon et al. (2003) Role of acetylated human AP-endonuclease (APE1/Ref-1) in regulation of the parathyroid hormone gene. EMBO J 22:6299-309

Showing the most recent 10 out of 80 publications