Age-related changes in the regulation of stress reponse genes are due to altered structure and function of their trans-acting regulators. Our long-range goal is to identify the mechanisms for the age-relted effects on responses to stress factors. We propose that cytokines and reactive oxygen species (ROS), shown to increase in aging, affect the activity of pathways tranducing these mediators' singals, so that aging tissues exhibit characteristics of chronic stress. Our data suggest that the synthesis of C/EBPalpha and C/EBPbeta isoforms is regulated by lipopolysaccharide (LPS); that this involves alternative translational initiation(ATI) at specific in-frame AUG codons withinthe same mRNA; and that ATI characteristic of an inflammatory response in young livers occurs constitutively in aged animals. We propose that ATI occurs via a leaky ribosomal scanning (LRS) mechanism that is linked to specific signal transduction pathways.
Specific aim 1 will determine whether the regulation of C/EBP isoform synthesis involves ATI of their mRNAs in young livers and whether ATI is altered in the aged liver.
Specific Aim 2 will test whether ATI is constitutive level of activity.
Specific Aim 3 demonstrate a linkage of C/EBP isoform synthesis and activation to oxidative stress. We propose that generators of ROS, such as DNA-damaging agents, may trigger the signal pathways that regulate ATI. The role of C/EBP in AP- endonuclease (APE) induction by HOC1, in cellular adaptation to DNA-damaging agents, and APE's inducibility by LPS in aging will be examined. Collaborative experiments to study the effects of mitochondrial DNA-damaged agents, on the regulation of C/EBP isoform synthesis are based on the hypothesis that age-associated increases in ROS may, in part, be due to radicals produced by mitochondrial DNA damage;. We will determine whether p21 (Cip1) is a stress response gene whose expression and regulation involved interaction of C/EBPs with its promoter binding sites.
Specific Aim 4 will test the hypothesis that caloric restriction affects regulation of the biological process involving responses to ROS. The data gained by this project lay the foundation for future studies on tissue specific responses to stress, in vivo, and their susceptibility to age-related diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
3P01AG010514-07S1
Application #
6295594
Study Section
Project Start
1998-12-01
Project End
1999-05-31
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
7
Fiscal Year
1999
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