The working hypothesis of this Program Project is that aging comprises a gradual progression of declines in tissue function caused by changes in basic intrinsic processes, and that these often alter the structure and function of key regulatory molecules for genes whose products are vital to protect against stress-mediated tissue damage and proliferative activation. Our long-term goal is to determine whether aging affects the structure and function of regulatory factors that control gene expression and proliferation.
The Specific Aims of the initial project period are to determine whether (a) the activity of key regulatory or trans-acting factors for genes that respond to inflammation, injury, or stress are altered by aging; and (b) whether functional failure of cells and tissues in aging is due to attenuated activity of these regulatory molecules. The scientific five components of this Program Project will address these two broad aims using a variety of approaches to examine the effects of aging on intrinsic processes in several rodent tissues. Project 1 (JP) will focus on age-related changes in regulation of the acute phase response to bacterial lipopolysaccharide (LPS) in the mouse liver, while Project 4 (EAT) will examine age-associated changes in transcriptional regulation of genes encoding ribosomal components of LPS-stimulated B lymphocytes. Both the acute phase and proliferative responses are markedly reduced in aged rodents. Project 3 (RP-P) and Project 2 (JL) will focus on age-associated deterioration in the central nervous system: Project (3) will concentrate on reduced efficiency of nerve growth factor and its receptors, and the interactions of this growth factor with corticosteroids in the hippocampus and basal forebrain; Project 5 (PW) will examine mechanisms responsible for altered serum/lymph hyaluronate levels with aging and their possible role as a basis for reduced proliferative response in B lymphocytes and neuronal cells. Additionally, Administrative and Molecular Biology Cores will provide administrative oversight and molecular biological facilities and expertise to the five scientific projects. These five projects complement one another both mechanistically and theoretically. Programmatic interactions will include: sharing tissues among the various investigators to reduce animal costs; consulting with one another both as to experimental design, methodological approaches, and data analysis; and active collaborations. By bringing a range of different approaches to bear on various age-related changes in stress responses in different experimental systems, we will more clearly discern common regulatory themes that effect the decline in proper tissue functions with age.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG010514-04
Application #
2051743
Study Section
Biological and Clinical Aging Review Committee (BCA)
Project Start
1992-06-01
Project End
1997-05-31
Budget Start
1995-06-10
Budget End
1996-05-31
Support Year
4
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Biochemistry
Type
Schools of Medicine
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

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