Humans and other mammals have a constant and absolute requirement for O2 and tissue oxygenation is maintained within a narrow physiologic range. In many disease states, however, O2 homeostasis is disrupted Hypoxia is a major factor contributing to the pathophysiology of heart attack, stroke, pulmonary hypertension, and other important causes of morbidity. The broad, long objective of the proposed research is to increase our understanding of the role of the transcriptional regulator hypoxia-inducible factor 1 (HIF-1) in the maintenance of cellular and systematic 02 homeostasis. HIF-1 is a heterodimeric basic-helix-loop- helix PAS transcription factor consisting of HIF-1alpha and HIF-1beta subunits. HIF-1alpha expression and HIF-1 transcriptional activity increase exponentially as cellular O2 concentration is decreased. Several dozen target genes that are transactivated by HIF-1 have been identified including those encoding erythropoietin, glucose transporters, glycolytic enzymes, and vascular endothelial growth factor. The products of these genes either increase O2 delivery or allow metabolic adaptation to reduced O2 availability. HIF-1 is required for cardiac and vascular development and embryonic survival. In fetal and postnatal life, HIF-1 is required for a variety of physiological responses to chronic hypoxia.
The specific aims of this proposal are: to determine the role of HIF-1 in the pathogenesis of cerebral ischemia and analyze the expression of HIF-1 in ischemic kidney and liver; to determine the involvement of HIV-1 in wound healing; and to elucidate the signal transduction pathways by which insulin-like growth factor-1 receptor and V-SRC activity induce expression of HIF-1. The knowledge gained from the proposed experiments will be relevant to the treatment of many clinical conditions in which hypoxia or ischemia plays an important pathophysiologic role.
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