Grant: Discovery Grants Program - Individual

For decades, modern biological research has progressed down an increasingly microscopic scale, where understanding cellular, molecular and genetic mechanisms has been the dominant theme. Although important new discoveries toward understanding basic cellular mechanisms have resulted, this genomic perspective has been less predictive than anticipated on understanding body function, and surprisingly few medical advances have resulted. Integrative physiologists, who focus on understanding the functions of and relationships between organ systems, are now re-taking center stage in the pursuit of understanding biological function. One important biological function that still requires the research efforts of integrative physiologists is the control of breathing. Breathing is a fundamental homeostatic behavior we perform over 700 times/hour, largely without conscious control, keeping blood gases (e.g., CO2 and O2) within narrow ranges. The control of breathing is mediated through complex coordination between the lungs, heart, and brain. This integrated control includes interactions between (a) ventilation for the exchange of blood gases, (b) cardiovascular regulation of blood flow to the brain, and (c) stimulation of respiratory chemoreceptors, which detect changes in blood gases (e.g., high CO2 and low O2) and mediate the feedback control of breathing. In this proposal, I explore the integrated coordination between the respiratory, cardiovascular, and cerebrovascular systems in contexts of work, rest and play. Specifically, the proposed program of research focuses on developing novel methods and perspectives to understand how healthy humans respond to blood gas challenges, particularly across diverse contexts including (a) trekking and sleeping at altitude, where individuals are susceptible to acute mountain sickness and sleep apnea, and (b) workplace exposures to low oxygen (hypoxia). Following these investigations into the interactions and interrelationships between the respiratory, cardiovascular, and cerebrovascular systems, a comprehensive and integrative picture of the control of breathing will emerge. In addition, the development of new, portable, and simple methodologies and models will increase our capacity to make meaningful measurements in the lab, clinic, and austere field environments in large groups of healthy people. Through arriving at a comprehensive understanding of the normal human responses to blood gas challenges, we can better apply integrative perspectives to understanding body function in health and disease. A number of clear outcomes will emerge, including developing a better understanding of (a) who will get sick at altitude and how to prevent it, which will have profound implications for trekking, climbing, and military forays to altitude and (b) the long term effects of repeated exposures to hypoxia in the workplace.