Norepinephrine (NE) is a crucial catecholamine neurotransmitter/hormone mediating a wide range of physiological responses. Alterations in NE neurotransmission are associated with several prevalent disorders, including cardiovascular disorders such as hypertension/hypotension, neuropsychiatric disorders, such as depression and in Parkinson's disease. Regulation of the expression of NE-biosynthetic enzymes, tyrosine hydroxylase (TH) and dopamine beta-hydroxylase (DBH), is a key mechanism of regulation of the NE systems.
The specific aims of this proposal are: 1.) Determine the kinetics and the persistence of activation of TH and DBH transcription in rat locus coeruleus with different duration or repetitions of immobilization stress. 2.) Examine the dynamics of pathways involved in transcriptional activation of TH and DBH gene expression in locus coeruleus and adrenal medulla with different durations or repetitions of stress. 3.) Identify the induction of de novo synthesis of transient or long-lasting transcription factors in rat adrenal medulla and locus coeruleus associated with regulation of TH and DBH gene expression by exposure to single and repeated immobilization stress. 4.) Begin to characterize the mechanisms by which the above observed stress responsive factors cross-talk to regulate TH and DBH gene expression. Specifically examine the interaction of AP-l factors and Egr1 on the regulation of TH transcription. The results will provide a crucial understanding of the different transcriptional mechanisms of activation of gene expression of catecholamine producing systems in the CNS and the periphery with acute and repeated exposure to stressful situations. These findings will contribute to the development of new strategies to prevent the harmful maladaptive changes in catecholamine neurotransmission, while enhancing its beneficial adaptive aspects

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS028869-12
Application #
6774752
Study Section
Special Emphasis Panel (ZRG1-IFCN-2 (01))
Program Officer
Murphy, Diane
Project Start
1990-08-01
Project End
2007-05-31
Budget Start
2004-06-01
Budget End
2005-05-31
Support Year
12
Fiscal Year
2004
Total Cost
$297,350
Indirect Cost
Name
New York Medical College
Department
Biochemistry
Type
Schools of Medicine
DUNS #
041907486
City
Valhalla
State
NY
Country
United States
Zip Code
10595
Papanikolaou, Nikolaos A; Tillinger, Andrej; Liu, Xiaoping et al. (2014) A systems approach identifies co-signaling molecules of early growth response 1 transcription factor in immobilization stress. BMC Syst Biol 8:100
Serova, L I; Nostramo, R; Veerasirikul, M et al. (2011) Varied mechanisms of oestradiol-mediated regulation of dopamine ?-hydroxylase transcription. J Neuroendocrinol 23:168-76
Tillinger, Andrej; Sollas, Anne; Serova, Lidia I et al. (2010) Vesicular monoamine transporters (VMATs) in adrenal chromaffin cells: stress-triggered induction of VMAT2 and expression in epinephrine synthesizing cells. Cell Mol Neurobiol 30:1459-65
Sabban, Esther L; Maharjan, Shreekrishna; Nostramo, Regina et al. (2010) Divergent effects of estradiol on gene expression of catecholamine biosynthetic enzymes. Physiol Behav 99:163-8
Kvetnansky, Richard; Sabban, Esther L; Palkovits, Miklos (2009) Catecholaminergic systems in stress: structural and molecular genetic approaches. Physiol Rev 89:535-606
Liu, Xiaoping; Serova, Lidia; Kvetnansky, Richard et al. (2008) Identifying the stress transcriptome in the adrenal medulla following acute and repeated immobilization. Ann N Y Acad Sci 1148:1-28
Cheng, Shu-Yuan; Serova, Lidia I; Glazkova, Dina et al. (2008) Regulation of rat dopamine beta-hydroxylase gene transcription by early growth response gene 1 (Egr1). Brain Res 1193:1-11
Sabban, Esther L (2007) Catecholamines in stress: molecular mechanisms of gene expression. Endocr Regul 41:61-73
Gueorguiev, Volodia D; Cheng, Shu-Yuan; Sabban, Esther L (2006) Prolonged activation of cAMP-response element-binding protein and ATF-2 needed for nicotine-triggered elevation of tyrosine hydroxylase gene transcription in PC12 cells. J Biol Chem 281:10188-95
Sabban, Esther L; Liu, Xiaoping; Serova, Lidia et al. (2006) Stress triggered changes in gene expression in adrenal medulla: transcriptional responses to acute and chronic stress. Cell Mol Neurobiol 26:845-56

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