The long-term objective of my research is to determine the neurobiological mechanisms underlying the significant and independent risk for cardiovascular (CV) morbidity/mortality resulting from obstructive sleep apnea (OSA). Aberrant sympathetic activation is a pathophysiologic hallmark of OSA, but the neurobiological mechanisms that regulate sympathetic activities across sleep-wake states are poorly understood. This lack of knowledge has thwarted attempts to devise specific therapeutic strategies for the CV consequences of OSA. My research is focused on the pedunculopontine tegmental nucleus (PPT), a cluster of neurons in the rostral pons. The PPT has a well-established role in controlling rapid eye movement (REM) sleep, a state associated with autonomic instability. Our laboratory developed novel data indicating that local stimulation of PPT neurons elicits CV and sympathoexcitatory activities (e.g., elevated blood pressure, tachycardia, and increased renal sympathetic nerve activity). I hypothesize that there is a sympathetic modulating region of the PPT (i.e., a PPT- SMR) that significantly and differentially regulates sympathetic activities across sleep-wake states (such as REM sleep) and that altered PPT-SMR function in OSA represents a mechanistic link between OSA and aberrant activation of the sympathetic nervous system. I have a strong foundation of knowledge/competency relevant to studying CV pathophysiology, and in this Pathway to Independence Award application I propose two years of additional training in neuroscience and the assessment of CV reflexes, which will be important for launching an innovative R00 investigation to determine how the PPT-SMR modulates CV function across behavioral states in an experimental model of OSA. In the K99 phase, I will conduct experiments in anesthetized rats to determine the location(s), neurochemical phenotype, and projections of PPT-SMR neurons. I will also define the role of PPT-SMR neurons in mediating/modulating sympathetic responses to acute hypoxia. In the R00 phase, I will determine the impact of PPT-SMR lesion and chronic intermittent hypoxia (CIH) on CV function across behavioral states (non-REM sleep, REM sleep, and wakefulness) in rats. Both the K99 and R00 phase investigations represent important foundations for my future R01 initiatives to define neurobiology of the CV consequences of OSA.

Public Health Relevance

Cardiovascular (CV) disease secondary to obstructive sleep apnea (OSA) poses a serious public health problem. Approximately 18 million Americans are afflicted with OSA, and CV disease is a leading cause of death worldwide. This research is focused on understanding the role of the pedunculopontine tegmental nucleus (PPT) in the control of the sympathetic nervous system. This research is consistent with the NINR's goal to support basic research to improve our knowledge of the underlying biological systems associated with human disease (NINR Strategic Plan, 2011). The elucidated neurobiological mechanisms represent potential targets for therapies preventing CV morbidity and mortality.

Agency
National Institute of Health (NIH)
Institute
National Institute of Nursing Research (NINR)
Type
Career Transition Award (K99)
Project #
1K99NR014369-01A1
Application #
8634208
Study Section
National Institute of Nursing Research Initial Review Group (NRRC)
Program Officer
Huss, Karen
Project Start
2013-09-27
Project End
2015-08-31
Budget Start
2013-09-27
Budget End
2014-08-31
Support Year
1
Fiscal Year
2013
Total Cost
$99,295
Indirect Cost
$7,355
Name
University of Illinois at Chicago
Department
Other Health Professions
Type
Schools of Nursing
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Fink, Anne M; Topchiy, Irina; Ragozzino, Michael et al. (2014) Brown Norway and Zucker Lean rats demonstrate circadian variation in ventilation and sleep apnea. Sleep 37:715-21