One of the best examples of adaptation to cardiovascular perturbations at the molecular level is the induction of tyrosine hydroxylase (TH) in adrenal glands and sympathetic ganglia in response to reserpine-induced hypotension. It has been shown that aging is associated with alterations in TH, the rate limiting enzymatic step in catecholamine (CA) synthesis. However, the role of TH gene expression in the age-related decline in cardiovascular homeostatic mechanisms remains to be elucidated. In the research described in this proposal, the hypothesis will be tested that aging animals are impaired in the ability to induce TH in response to reserpine because of alterations in mechanisms regulating TH gene expression. The specific objectives of this project are the following: 1. The induction of TH expression in vivo by reserpine will be compared in the adrenal glands of rats 4-30 months of age: Alterations in the TH protein will be measured with a specific antibody and correlated with the kinetics of TH activity and TH mRNA levels. The time course of induction of TH and TH mRNA will be compared in rats of different ages and correlated with rates of TH mRNA transcription. Translatability of TH mRNA will be correlated with alterations in TH protein and activity. Age-related alterations in pre-and post-synaptic parameters of neurotransmitters that regulate TH induction will also be correlated with age-related alterations in induction of TH and TH mRNA. 2. The induction of TH gene expression in vitro will be compared in cultured adrenal medullas isolated from different aged rats; the induction of TH and TH mRNA by dexamethasone and nicotinic receptor agonist will be compared. The time course and magnitude of induction of TH activity, TH protein levels and TH mRNA will be compared with rates of TH protein synthesis in situ. TH mRNA transcription will be measured and compared with time course and magnitude of induction of TH mRNA and TH activity. 3. The effects of dietary restriction on age-associated alterations in adrenal TH gene expression will be assessed. In the past several years, life-long caloric restriction, a treatment that increases the life-span of mammals, has become a tool to distinguish time-dependent effects from biological aging. Therefore, dietary restriction will be used to determine if age-related differences in modulation of TH gene expression by reserpine in vivo and in culture is integral to the aging process.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG009557-05
Application #
2050889
Study Section
Endocrinology Study Section (END)
Project Start
1993-08-07
Project End
1995-06-30
Budget Start
1994-02-10
Budget End
1995-06-30
Support Year
5
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
Corbitt, J; Vivekananda, J; Wang, S S et al. (1998) Transcriptional and posttranscriptional control of tyrosine hydroxylase gene expression during persistent stimulation of pituitary adenylate cyclase-activating polypeptide receptors on PC12 cells: regulation by protein kinase A-dependent and protein kinas J Neurochem 71:478-86
Mattammal, M B; Strong, R; Lakshmi, V M et al. (1995) Prostaglandin H synthetase-mediated metabolism of dopamine: implication for Parkinson's disease. J Neurochem 64:1645-54
Mattammal, M B; Strong, R; White 5th, E et al. (1994) Characterization of peroxidative oxidation products of dopamine by mass spectrometry. J Chromatogr B Biomed Appl 658:21-30
Burke, W J; Raghu, G; Strong, R (1994) Taxol protects against calcium-mediated death of differentiated rat pheochromocytoma cells. Life Sci 55:313-9
Wessels-Reiker, M; Basiboina, R; Howlett, A C et al. (1993) Vasoactive intestinal polypeptide-related peptides modulate tyrosine hydroxylase gene expression in PC12 cells through multiple adenylate cyclase-coupled receptors. J Neurochem 60:1018-29
Heydari, A R; Wu, B; Takahashi, R et al. (1993) Expression of heat shock protein 70 is altered by age and diet at the level of transcription. Mol Cell Biol 13:2909-18
Tumer, N; Hale, C; Lawler, J et al. (1992) Modulation of tyrosine hydroxylase gene expression in the rat adrenal gland by exercise: effects of age. Brain Res Mol Brain Res 14:51-6
Wessels-Reiker, M; Haycock, J W; Howlett, A C et al. (1991) Vasoactive intestinal polypeptide induces tyrosine hydroxylase in PC12 cells. J Biol Chem 266:9347-50