Respiration in mammals is a primal homeostatic process, regulating levels of oxygen (O2) and carbon dioxide (CO2) in blood and tissues and is crucial for life. Rhythmic respiratory movements must occur continuously throughout life and originate from neural activity generated by specially organized circuits in the brain stem constituting the respiratory central pattern generator (CPG). The respiratory CPG generates rhythmic patterns of motor activity that produce coordinated movements of the respiratory pump (diaphragm, thorax, and abdomen), controlling lung inflation and deflation, and upper airway muscles, controlling airflow. These coordinated rhythmic movements drive exchange and transport of O2 and CO2 that maintain physiological homeostasis of the brain and body. Uncovering complex multilevel and multiscale mechanisms operating in the respiratory system, leading to mechanistic understanding of breathing, including breathing in different disease states requires a Physiome-type approach that relies on the development and explicit implementation of multiscale computational models of particular organs and physiological functions.
The specific aims of this multi-institutional project are: (1) develop a Physiome-type, predictive, multiscale computational model of neural control of breathing that links multiple physiological mechanisms and processes involved in the vital function of breathing but operating at different scales of functional and structural organization, (2) validate this model in a series of complementary experimental investigations and (3) use the model as a computational framework for formulating predictions about possible sources and mechanisms of respiratory pattern alteration associated with heart failure. The project brings together a multidisciplinary team of scientists with long standing collaboration and complementary expertise in respiration physiology, neuroscience and translational medical studies (Thomas E. Dick, Case Western Reserve University;Julian F.R. Paton, University of Bristol, UK;Robert F. Rogers, Drexel University;Jeffrey C. Smith, NINDS, NIH, intramural), mathematics, system analysis and bioengineering (Alona Ben-Tal, Massey University, NZ), and computational neuroscience and neural control (Ilya A. Rybak, Drexel University). The end result of our proposed cross-disciplinary modeling and experimental studies will be the development and implementation of a new, fully operational, multiscale model of the integrated neurophysiological control system for breathing based on the current state of physiological knowledge. This model can then be used as a computational framework for formulating predictions about possible neural mechanisms of respiratory diseases and suggesting possible treatments.

Public Health Relevance

The ultimate goal of this project is to develop a multiscale model of neural control of breathing that can be used as a computational framework for formulating predictions about possible neural mechanisms of respiratory diseases and suggesting possible treatments. The project will specially address respiration related problems associated with heart failure.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS069220-04
Application #
8535256
Study Section
Modeling and Analysis of Biological Systems Study Section (MABS)
Program Officer
Liu, Yuan
Project Start
2010-09-01
Project End
2015-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
4
Fiscal Year
2013
Total Cost
$544,390
Indirect Cost
$105,127
Name
Drexel University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
002604817
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Geraldes, Vera; Goncalves-Rosa, Nataniel; Liu, Beihui et al. (2014) Chronic depression of hypothalamic paraventricular neuronal activity produces sustained hypotension in hypertensive rats. Exp Physiol 99:89-100
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Shevtsova, Natalia A; Büsselberg, Dietrich; Molkov, Yaroslav I et al. (2014) Effects of glycinergic inhibition failure on respiratory rhythm and pattern generation. Prog Brain Res 209:25-38
Dick, Thomas E; Hsieh, Yee-Hsee; Dhingra, Rishi R et al. (2014) Cardiorespiratory coupling: common rhythms in cardiac, sympathetic, and respiratory activities. Prog Brain Res 209:191-205
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Oliveira-Sales, Elizabeth B; Toward, Marie Ann; Campos, Ruy R et al. (2014) Revealing the role of the autonomic nervous system in the development and maintenance of Goldblatt hypertension in rats. Auton Neurosci 183:23-9
Moraes, Davi J A; Machado, Benedito H; Paton, Julian F R (2014) Specific respiratory neuron types have increased excitability that drive presympathetic neurones in neurogenic hypertension. Hypertension 63:1309-18

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