The prevalence of Obstructive Sleep Apnea (OSA) is increasing dramatically in the U.S. representing a serious health risk. The primary consequence of airway obstruction during sleep is to cause hypoxemia which stimulates the carotid body, leading to increased respiratory drive until arousal from sleep restores upper airway patency. This project proposes to determine the mechanisms by which the carotid body senses and responds to the repetitive intermittent periods of hypoxemia in OSA. Based on the critically important role of acetylcholine as an excitatory neurotransmitter in the carotid body's chemotransduction of hypoxia, it is hypothesized 1) that the repetitive intermittent hypoxia of OSA alters cholinergic transduction pathways in the carotid body, and 2) that the sensitivity of the carotid body is determined genetically.
Specific Aim 1 will examine the impact of repetitive intermittent hypoxia during sleep on carotid body function in a novel, murine model of sleep disordered breathing.
Specific Aim 2 will investigate the pattern of acetylcholine and other neurotransmitter release from the carotid body, as well as recording carotid sinus nerve activity, in response to repetitive intermittent hypoxia.
Specific Aim 3 will use immunohistochemical and patch clamp analyses to determine if neuronal nicotinic acetylcholine receptors (nAChRs) can account for differential hypoxic responsiveness between mouse strains with differential hypoxic responsiveness and determine whether repetitive intermittent hypoxia upregulates expression of subtypes of nAChRs.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL066324-03
Application #
6527697
Study Section
Special Emphasis Panel (ZHL1-CSR-H (S1))
Program Officer
Twery, Michael
Project Start
2000-09-30
Project End
2004-08-31
Budget Start
2002-09-01
Budget End
2003-08-31
Support Year
3
Fiscal Year
2002
Total Cost
$286,125
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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Campen, M J; Shimoda, L A; O'Donnell, C P (2005) Acute and chronic cardiovascular effects of intermittent hypoxia in C57BL/6J mice. J Appl Physiol 99:2028-35
Yamaguchi, Shigeki; Lande, Boris; Kitajima, Toshimitsu et al. (2004) Patch clamp study of mouse glomus cells using a whole carotid body. Neurosci Lett 357:155-7
Polotsky, Vsevolod Y; Smaldone, Marc C; Scharf, Matthew T et al. (2004) Impact of interrupted leptin pathways on ventilatory control. J Appl Physiol 96:991-8
Rubin, Arnon E; Polotsky, Vsevolod Y; Balbir, Alexander et al. (2003) Differences in sleep-induced hypoxia between A/J and DBA/2J mouse strains. Am J Respir Crit Care Med 168:1520-7
Yamaguchi, Shigeki; Balbir, Alexander; Schofield, Brian et al. (2003) Structural and functional differences of the carotid body between DBA/2J and A/J strains of mice. J Appl Physiol 94:1536-42
Polotsky, Vsevolod Y; Li, Jianguo; Punjabi, Naresh M et al. (2003) Intermittent hypoxia increases insulin resistance in genetically obese mice. J Physiol 552:253-64
Campen, Matthew J; Tagaito, Yugo; Jenkins, Todd P et al. (2002) Phenotypic differences in the hemodynamic response during REM sleep in six strains of inbred mice. Physiol Genomics 11:227-34