HIF-1 AND HYPOXIC RESPONSE IN DEVELOPMENT AND DISEASE

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The hypoxia-inducible factor (HIF) is a transcription factor that controls the mammalian cellular transcriptional response to low oxygen tension by up-regulating genes including glycolytic enzymes and angiogenic factors, such as the vascular endothelial growth factor (VEGF). Under normal oxygen tensions, the pathway is negatively regulated by posttranslational proteasomal degradation of HIF-alpha subunits in a pathway requiring prolyl-hydroxylase domain (PHD) containing enzyme modification followed by von-Hippel Lindau (VHL) tumor suppressor polyubiquitination (pVHL). Murine knockouts of HIF, pVHL, PHD, and VEGF have demonstrated the essential role of these hypoxic response pathway proteins in development. Conditional deletion of these genes in a wide range of tissues has further shown that ablation or overexpression of the pathway has profound in vivo effects, with important implications for physiology, pathology, and tumor biology. Despite these recent advances in the understanding of how cells respond to low oxygen tension, the modulatory effect of HIF-1 on mitochondria and on cells as a whole is not fully understood. We propose using electron microscopy to look at primary murine T cells with and without HIF-1 alpha which have been cultured in vitro in normoxic or hypoxic conditions. Specifically, we would like to look at organelle morphology (including mitochondria, which HIF-1 has been shown to modulate), and nuclear to cytoplasmic ratio. We feel this analysis may yield new and exciting information on how HIF-1 maximizes cellular metabolic efficiency in the face of oxygen deficit.