Abstract

The current renewal will determine the cellular mechanisms underlying agonist-induced sensitization and the biochemical, structural, and physiological consequences of pharmacologic overstimulation of cardiac fetal beta-receptors by terbutaline. They will then go on to evaluate what cellular and molecular events occur within the postnatal period to replace fetal agonist-induced sensitization with the mature mechanism, agonist-induced desensitization.
The aims are: 1. To determine what cellular mechanisms govern the ontogeny of agonist-induced beta-receptor downregulation and uncoupling from response elements in the developing heart; 2. To determine the mechanisms underlying fetal agonist induced sensitization of cardiac adenylyl cyclase; to determine the structural and functional consequences of fetal overstimulation with terbutaline during the period in which desensitization cannot be evoked.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD009713-25
Application #
6608180
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Program Officer
Lock, Allan
Project Start
1976-06-15
Project End
2005-05-31
Budget Start
2003-06-01
Budget End
2005-05-31
Support Year
25
Fiscal Year
2003
Total Cost
$242,550
Indirect Cost

  Institution

Name
Duke University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705

  Publications

Kreider, Marisa L; Tate, Charlotte A; Cousins, Mandy M et al. (2006) Lasting effects of developmental dexamethasone treatment on neural cell number and size, synaptic activity, and cell signaling: critical periods of vulnerability, dose-effect relationships, regional targets, and sex selectivity. Neuropsychopharmacology 31:12-35
Aldridge, Justin E; Meyer, Armando; Seidler, Frederic J et al. (2005) Developmental exposure to terbutaline and chlorpyrifos: pharmacotherapy of preterm labor and an environmental neurotoxicant converge on serotonergic systems in neonatal rat brain regions. Toxicol Appl Pharmacol 203:132-44
Meyer, Armando; Seidler, Frederic J; Aldridge, Justin E et al. (2005) Developmental exposure to terbutaline alters cell signaling in mature rat brain regions and augments the effects of subsequent neonatal exposure to the organophosphorus insecticide chlorpyrifos. Toxicol Appl Pharmacol 203:154-66
Kreider, Marisa L; Aldridge, Justin E; Cousins, Mandy M et al. (2005) Disruption of rat forebrain development by glucocorticoids: critical perinatal periods for effects on neural cell acquisition and on cell signaling cascades mediating noradrenergic and cholinergic neurotransmitter/neurotrophic responses. Neuropsychopharmacology 30:1841-55
Slotkin, Theodore A; Oliver, Colleen A; Seidler, Frederic J (2005) Critical periods for the role of oxidative stress in the developmental neurotoxicity of chlorpyrifos and terbutaline, alone or in combination. Brain Res Dev Brain Res 157:172-80
Kreider, Marisa L; Levin, Edward D; Seidler, Frederic J et al. (2005) Gestational dexamethasone treatment elicits sex-dependent alterations in locomotor activity, reward-based memory and hippocampal cholinergic function in adolescent and adult rats. Neuropsychopharmacology 30:1617-23
Rhodes, Melissa C; Seidler, Frederic J; Qiao, Dan et al. (2004) Does pharmacotherapy for preterm labor sensitize the developing brain to environmental neurotoxicants? Cellular and synaptic effects of sequential exposure to terbutaline and chlorpyrifos in neonatal rats. Toxicol Appl Pharmacol 195:203-17
Kreider, Marisa L; Seidler, Frederic J; Cousins, Mandy M et al. (2004) Transiently overexpressed alpha2-adrenoceptors and their control of DNA synthesis in the developing brain. Brain Res Dev Brain Res 152:233-9
Rhodes, Melissa C; Seidler, Frederic J; Abdel-Rahman, Ali et al. (2004) Terbutaline is a developmental neurotoxicant: effects on neuroproteins and morphology in cerebellum, hippocampus, and somatosensory cortex. J Pharmacol Exp Ther 308:529-37
Kreider, Marisa L; Seidler, Frederic J; Slotkin, Theodore A (2004) Beta-adrenoceptor modulation of transiently overexpressed alpha 2-adrenoceptors in brain and peripheral tissues: cellular mechanisms underlying the developmental toxicity of terbutaline. Brain Res Bull 62:305-14

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