My research has two major objectives: the first is directed toward understanding receptor mechanisms involved in regulating tyrosine hydroxylase (TH) gene expression, the rate limiting enzyme in the synthesis of catecholamines. The latter substances are crucially involved in various life-sustaining functions and are implicated in diseases such as hypertension, depression and Parkinson's disease. We are examining the signal transduction mechanisms that mediate the effects of selected neurotransmitter and neuromodulators on TH gene expression in a cultured adrenal chromaffin cell line. Most recently, we have focused on vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide (PACAP) receptors and glucocorticoid receptors. We have investigated both transcriptional and post-transcriptional responses to PACAP and VIP and found that the PAC1 receptor distinguishes between the two agonists by stabilizing TH mRNA in response to PACAP, but not VIP. We are investigating intracellular signaling pathways in this response. We also recently identified the glucocorticoid responsive element in the promoter region of the TH gene. We are examining how second messenger pathways that are stimulated by neuropeptide receptors modulate the transcriptional responses to glucocorticoids.
The second research objective is directed toward understanding the role of oxidative stress in the aging brain. One project is aimed at determining how reactive catecholamine metabolites contribute to neuropathology of aging and Parkinson's disease. We are particularly interested in the role that 3,4-dihydroxyphenylacetaldehyde (DOPAL) plays in degeneration of dopamine neurons. This highly reactive metabolite of dopamine becomes elevated in Parkinson's disease and is neurotoxic. Rotenone, a pesticide that reproduces the pathology of Parkinson's disease in rats, has been shown to elevate DOPAL in cultured cells. DOPAL is believed to be cleared by the mitochondrial aldehyde dehydrogenase (ALDH2). We have developed an ALDH2 knockout mouse to determine the role of this enzyme in DOPAL catabolism. We are also using this new mouse model to study the role of DOPAL in the pathology of Parkinson's disease.
My laboratory is one of three funded by the NIA Aging Interventions Testing Program that reported the landmark finding that rapamycin extends mammalian longevity, even when treatment is started late in life (Nature, 2009; J. Gerontol. 2011). Subsequent studies revealed that rapamycin delays or prevents pathology in several animal models of age-related diseases including Alzheimer's and Parkinson's diseases.
Hasty P, Livi CB, Dodds SG, Jones D, Strong R, Javors M, Fischer KE, Sloane L, Murthy K, Hubbard G, Sun L, Hurez V, Curiel TJ, Sharp ZD. Rapa restores a normal life span in a FAP mouse model. Cancer Prev Res (Phila). 2014 Jan;7(1):169-78.
Miller RA, Harrison DE, Astle CM, Fernandez E, Flurkey K, Han M, Javors MA, Li X, Nadon NL, Nelson JF, Pletcher S, Salmon AB, Sharp ZD, Van Roekel S, Winkleman L, Strong R. Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. Aging Cell. 2013 Dec 17.
Harrison DE, Strong R, Allison DB, Ames BN, Astle CM, Atamna H, Fernandez E, Flurkey K, Javors MA, Nadon NL, Nelson JF, Pletcher S, Simpkins JW, Smith D, Wilkinson JE, Miller RA. Acarbose, 17-α-estradiol, and nordihydroguaiaretic acid extend mouse lifespan preferentially in males. Aging Cell. 2014 Apr;13(2):273-82.
Strong R, Miller RA, Astle CM, Baur JA, de Cabo R, Fernandez E, Guo W, Javors M, Kirkland JL, Nelson JF, Sinclair DA, Teter B, Williams D, Zaveri N, Nadon NL, Harrison DE. Evaluation of resveratrol, green tea extract, curcumin, oxaloacetic acid, and medium-chain triglyceride oil on life span of genetically heterogeneous mice. J Gerontol A Biol Sci Med Sci. 2013 Jan;68(1):6-16.
Livi CB, Hardman RL, Christy BA, Dodds SG, Jones D, Williams C, Strong R, Bokov A, Javors MA, Ikeno Y, Hubbard G, Hasty P, Sharp ZD. Rapamycin extends life span of Rb1+/- mice by inhibiting neuroendocrine tumors. Aging (Albany NY). 2013 Feb;5(2):100-10.