ABSTRACT Millions of people in the United States have cardiopulmonary diseases marked by chronic hypoxia, a persistent reduction in oxygen availability and delivery to cells and tissues. In patients with diseases such as severe chronic obstructive pulmonary disease or advanced heart failure, chronic hypoxia is associated with increased morbidity and mortality. Little is known about how cells and tissues sense and adapt to chronic hypoxia. This proposal outlines a five-year K08 Mentored Clinical Scientist Research Career Development Award that will address this question and prepare me to become an independent physician-scientist with a focus on oxygen metabolism, lipid homeostasis, and cardiovascular disease. My goal in seeking this career development award is to acquire the robust knowledge and technical expertise I need to uncover the mechanisms of oxygen sensing and adaptation in mammals, which will open new therapeutic avenues to alleviate the impact of chronic hypoxia. I hypothesize that sterol regulatory element-binding protein 1 (SREBP1), which is a basic helix-loop-helix leucine zipper transcription factor, is an evolutionarily conserved oxygen sensor that mediates organismal adaptation to chronic hypoxia by monitoring oxygen-dependent changes in lipid saturation as an indirect measure of low oxygen availability. My preliminary data show that remnants of the yeast SREBP1-dependent oxygen sensing pathway are present in mammals and that SREBP1 is activated in chronic hypoxia. I hypothesize that SREBP1 promotes the transcription of genes that allow for cellular adaptation to chronic hypoxia by binding to various promoter regions, including hypoxia response elements and E-box domains (Aim 1). I also hypothesize that the oxygen sensing mechanism of SREBP1 is mediated through changes in fatty acid desaturation in chronic hypoxia (Aim 2). Finally, I hypothesize that SREBP-1c is a critical mediator of fatty acid uptake and utilization in the liver as mechanism to restore lipid homeostasis in chronic hypoxia (Aim 3). This research training will be conducted under the mentorship of Dr. Isha Jain, an oxygen metabolism expert who demonstrated the therapeutic potential of hypoxia for mitochondrial disease, with co-mentorship from Dr. Robert Mahley, an expert in lipid biology and cardiovascular and neurological diseases with a long track record of mentorship. I have assembled a team of highly accomplished advisors with expertise in hypoxia signaling in C. elegans, SREBP biology, lipid metabolism, and functional genomics. My training plan has been carefully structured to provide me with mentorship and robust research training in advanced techniques in molecular biology, bioinformatics, systems biology, and animal models of disease. My development plan will help me gain important skills in laboratory management, leadership, and scientific communication. Completing the research training program and obtaining the skill sets outlined in this K08 career devel...