The most important consequence of lung disease is hypoxemia. This research program continues its commitment ot understanding the causes and effects of hypoxemia in health and disease. We propose a series of projects, most of which have existed in and evolved from the present grant cycle, that have the overall objective of understanding how structural elements of the O2 transport chain determine and regulate O2 transport. The program is interdisciplinary and interdepartmental, =with investigators from the UCSD Departments of medicine, Bioengineering and Mathematics, and from University of California, Davis. As previously, we integrate theoretical considerations, cellular and molecular approaches, organ level studies, whole animal work and measurements in intact man. Studies encompass normal tissues, models of disease, and several human disease states. Project 1 (Wagner) deals with mechanisms of maximal O2 transport limitation; Project 2 (Mathieu-Costello) relates skeletal muscle structure to its energetic function; Project 3 (Poole) examines structure-function relations and O2 transport in the diaphragm in heath and disease; Project 4 (Powell) continues to define mechanisms of chemoreceptor response to hypoxia at the system and organ level while Project 5 (Hempleman) addresses the same issues at a cellular and subcellular level. The five projects are supported by the same cores as in the present cycle except that the electronics core has been amalgamated with the computing core to reduce costs, resulting in three cores; morphology/ morphometry, electronics/computing and administrative. All Projects except 3 and 5 are continuations of existing projects, and are led by the same investigators as in the current cycle; Projects 3 and 5 are proposed by individuals who already feature prominently in the present grant cycle as coinvestigators and who have now matured to project leadership within our research group.