In 2002 a draft sequence of the mouse genome was published and the NIH described this as "the genetic blueprint for the most important animal model in biomedical research." Every human gene has a mouse homologue and this enhances the probability that research using mice can provide novel insights into human disease. The long-term objective of this research program is to provide novel data concerning proteins that regulate sleep.
The Specific Aims were developed to address the mission of the agency and are directly relevant to the goals of the 2007 NHLBI Strategic Research Plan. All three aims address NHLBI challenge 1.1.b. "to identify intracellular targets of key signaling and transcriptional pathways in normal and pathological states." Pain disrupts sleep and there is an emerging understanding of the clinically significant interaction between sleep disruption, and pain perception.
Aim 1 will test the hypothesis that B6.V-Lepob mice lacking the ability to produce the protein leptin differ from congenic C57BL/6J (B6) mice in their response to nociceptive stimuli, before and after administration of cholinergic and adenosinergic agonists into the pontine reticular formation. By replacing leptin, Aim 1 also will determine whether leptin can restore the adenosinergic modulation of nociception.
Aim 2 focuses on adenosinergic and cholinergic activation of G proteins in prefrontal cortex and pontine reticular formation regions known to regulate sleep and breathing. Another family of proteins referred to as "Regulators of G protein Signaling" (RGS proteins) decrease the duration and strength of G protein actions.
Aim 2 will use transgenic mice to test the hypothesis that cholinergic and adenosinergic activation of G proteins in sleep-related brain regions differs between mice that are homozygous and heterozygous for RGS-insensitive proteins.
Aim 3 will provide functional data regarding RGS protein regulation of sleep phenotypes.
Aim 3 will test the hypothesis that RGS insensitive mice exhibit genotype- specific changes in cortical acetylcholine release, EEG power, sleep, and behavior caused by cortical delivery of cholinergic and adenosinergic agonists and antagonists. The three aims are conceptually unified by their shared focus on proteins as lower-level phenotypes that modulate higher-level phenotypes of sleep, nociception, and acetylcholine release in brain regions known to regulate sleep and breathing.

Public Health Relevance

The NIH National Center for Sleep Disorders web site notes that more than 70 million Americans have a sleep disorder. Thus, disordered sleep is a significant public health burden. This research program will provide new and needed information on brain proteins regulating sleep.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL065272-12
Application #
8501627
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Laposky, Aaron D
Project Start
1999-09-30
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
12
Fiscal Year
2013
Total Cost
$327,340
Indirect Cost
$115,282
Name
University of Michigan Ann Arbor
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Vanini, Giancarlo; Nemanis, Kriste; Baghdoyan, Helen A et al. (2014) GABAergic transmission in rat pontine reticular formation regulates the induction phase of anesthesia and modulates hyperalgesia caused by sleep deprivation. Eur J Neurosci 40:2264-73
Watson, S L; Watson, C J; Baghdoyan, H A et al. (2014) Adenosine A? receptors in mouse pontine reticular formation modulate nociception only in the presence of systemic leptin. Neuroscience 275:531-9
Filbey, William A; Sanford, David T; Baghdoyan, Helen A et al. (2014) Eszopiclone and dexmedetomidine depress ventilation in obese rats with features of metabolic syndrome. Sleep 37:871-80
Hambrecht-Wiedbusch, Viviane S; Mitchell, Melinda F; Firn, Kelsie A et al. (2014) Benzodiazepine site agonists differentially alter acetylcholine release in rat amygdala. Anesth Analg 118:1293-300
Janda, Allison; Lydic, Ralph; Welch, Kathleen B et al. (2013) Thermal hyperalgesia after sciatic nerve block in rat is transient and clinically insignificant. Reg Anesth Pain Med 38:151-4
Gettys, George C; Liu, Fang; Kimlin, Ed et al. (2013) Adenosine A(1) receptors in mouse pontine reticular formation depress breathing, increase anesthesia recovery time, and decrease acetylcholine release. Anesthesiology 118:327-36
Wathen, Asheley B; West, Emily S; Lydic, Ralph et al. (2012) Olanzapine causes a leptin-dependent increase in acetylcholine release in mouse prefrontal cortex. Sleep 35:315-23
Pal, Dinesh; Walton, Meredith E; Lipinski, William J et al. (2012) Determination of minimum alveolar concentration for isoflurane and sevoflurane in a rodent model of human metabolic syndrome. Anesth Analg 114:297-302
Watson, Christopher J; Lydic, Ralph; Baghdoyan, Helen A (2011) Sleep duration varies as a function of glutamate and GABA in rat pontine reticular formation. J Neurochem 118:571-80
Brummett, Chad M; Hong, Elizabeth K; Janda, Allison M et al. (2011) Perineural dexmedetomidine added to ropivacaine for sciatic nerve block in rats prolongs the duration of analgesia by blocking the hyperpolarization-activated cation current. Anesthesiology 115:836-43

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