The most important consequence of lung disease is hypoxemia resulting in impaired oxygen supply to the tissues, diminishing organ function. This research program continues its commitment to understanding the causes and effects of hypoxemia in health and disease. Three of the five projects address this at the level of the skeletal muscles. A fourth deals with cardiac consequences of hypoxia, and a fifth with neural plasticity in hypoxia. The same five project'leadersare proposed as in the current cycle (years 26-30), lending continuity to a productive program. However, experimental approaches have evolved to focus more onfundamental mechanisms of the hypoxic response. Yet there are also studies proposed to link these back to humans as a function of age and disease, making for an integrated approach to the problem of hypoxia. Project 1 (Wagner) focuses on the basic molecular mechanisms of muscle angiogenesis in response to hypoxia in health and disease; Project 2 (Mathieu-Costello) uses modern morphometric methods to assess regional myocardialOz availability and the impact of chronic hypoxia and aging on this; Project 3 (Richardson) examines the effects of aging on human muscle structure and function using integrative methods ranging from macroscopic imaging to molecular biological; Project 4 (Powell) addresses the effects of hypoxia on neural function involved in ventilatory control, integrating molecular and physiological tools; Project 5 (Hogan) investigates the role of Oaavailability on single muscle fiber function in vitro using a combination of imaging, functional, and molecular methods. The projects interact extensively,many formally asjoint efforts between project leaders with overlapping interests, and are supported by three cores (Tissue Imaging and Morphometry; Molecular Biology; Administration). Our collective goals are to better understand how Oatransport between the environment and the mitochondria of several key organs is regulated as a function of aging and disease, and in turn, how hypoxia itself modulates its own availability and thereby affects organ function in these same conditions. ^