Request for Funding

Medical Student Research Fellowship for Summer 2004

Mentor: Joseph A. Garcia, MD,PhD
Department: Internal Medicine
Room number: NB10-216
Mail Code: 8573
Phone number: 214-648-1646
E-mail: joseph.garcia@utsouthwestern.edu
Project title: Integrative Studies of Mice Lacking Hypoxia Sensing Transcription Factor 2
Animal subjects IACUC approved project number (where applicable): APN 0896-03-01-1

Project Type: animal-based research, basic research

Brief Description of Project:
The PAS domain is a conserved polypeptide motif found in proteins having diverse physiologic roles including maintenance of circadian rhythm, response to xenobiotic and hypoxic stress, and developmental patterning of the nervous system. Hypoxia inducible factor -1? (HIF-1?) is a PAS domain-containing protein and a transcription factor that activates a number of target genes in response to lowered tissue oxygen conditions (hypoxia). Endothelial PAS domain protein 1 (EPAS1, also known as HIF-2?), a novel member of the PAS family closely related to HIF-1?, is expressed at high levels in vascular endothelial cells, catecholamine-containing glomus cells, and pulmonary pneumocytes in the developing embryo. Previous studies of inbred strains of mice globally lacking EPAS1/HIF-2? noted embryonic lethality in mid-gestation with pathologic findings distinct from those of HIF-1? null mice that also died in mid-gestation. Despite the observation that HIF-1 and EPAS1/HIF-2 can bind to similar DNA regulatory sequences in putative target gene promoter regions, we hypothesize that EPAS1 has unique target genes that define its primary biological role in the adult mouse. Using a genetic breeding strategy, we have successfully generated adult mice that globally lack EPAS1/HIF-2?. These mice exhibit a characteristic syndrome that consists of metabolic abnormalities, increased oxidative stress, and altered gene expression patterns. Our efforts are focused on defining the physiologic role of EPAS1/HIF-2? in the adult mouse and on the molecular mechanism for EPAS1/HIF-2? function.

Previous Research Activities or Publications with Medical Students: Not applicable (no prior medical students)

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