The fundamental hypothesis guiding this proposal is that adenosine release during acute intermittent hypoxia (AIM) modulates the capacity for plasticity in respiratory motor control. Specifically, we postulate that adenosine 2A receptor activation profoundly modulates a well-established model of AlH-induced respiratory plasticity known as phrenic long-term facilitation (pLTF). Preliminary data have demonstrated that adenosine A2A receptor antagonists greatly enhance pLTF following AIM and that the relevant A2A receptors are located in cervical spinal regions associated with the phrenic motor nucleus. AlH-induced pLTF requires serotonin receptor activation and new protein synthesis, including new synthesis of brain derived neurotrophic factor (BDNF). BDNF activates its high affinity receptor tyrosine kinase, TrkB, subsequently leading to pLTF. Reactive oxygen species (specifically superoxide anions derived from NADPH oxidase) are necessary for pLTF, most likely by inhibition of serine/threonine protein phosphatases, an important inhibitory constraint to pLTF. The major goal during this project period is to test the specific hypothesis that A2A receptors modulate these same cellular/synaptic elements known to play critical roles in the mechanism of pLTF. A detailed understanding of mechanisms whereby A2A receptors modulate respiratory plasticity may guide the development of novel therapeutic approaches to treat patients with severe ventilatory control disorders, such as obstructive sleep apnea and respiratory insufficiency in patients with spinal cord injury or neurodegenerative disease (e.g., ALS).
Three specific aims will be pursued using a multidisciplinary approach:
Aim 1 : To test the hypothesis that spinal A2A receptor antagonists enhance pLTF by modulating cellular mechanisms normally giving rise to pLTF.
Aim 2 : To test the hypothesis that spinal A2A receptor antagonists enhance pLTF by a mechanism that requires reactive oxygen species formation.
Aim 3 : To test the hypothesis that spinal A2A receptor antagonists modulate serine-threonine protein phosphatase activity, thereby enhancing pLTF

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31HL092785-02
Application #
7783815
Study Section
Special Emphasis Panel (ZRG1-DIG-H (29))
Program Officer
Laposky, Aaron D
Project Start
2009-01-01
Project End
2010-12-31
Budget Start
2010-01-01
Budget End
2010-12-31
Support Year
2
Fiscal Year
2010
Total Cost
$45,180
Indirect Cost
Name
University of Wisconsin Madison
Department
Biology
Type
Schools of Veterinary Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Hoffman, M S; Mitchell, G S (2013) Spinal 5-HT7 receptors and protein kinase A constrain intermittent hypoxia-induced phrenic long-term facilitation. Neuroscience 250:632-43
Hoffman, M S; Mitchell, G S (2011) Spinal 5-HT7 receptor activation induces long-lasting phrenic motor facilitation. J Physiol 589:1397-407
Dale-Nagle, Erica A; Hoffman, Michael S; MacFarlane, Peter M et al. (2010) Spinal plasticity following intermittent hypoxia: implications for spinal injury. Ann N Y Acad Sci 1198:252-9
Hoffman, M S; Golder, F J; Mahamed, S et al. (2010) Spinal adenosine A2(A) receptor inhibition enhances phrenic long term facilitation following acute intermittent hypoxia. J Physiol 588:255-66