Our laboratory efforts are focused on identifying genetic components involved in the vertebrate response to lowered tissue oxygen conditions (hypoxia), and defining the role of these genetic factors in whole animal adult physiology. Hypoxia inducible factor 1a (HIF1a) is a transcription factor that activates a number of target genes in response to hypoxia. Endothelial PAS domain protein 1 (EPAS1), also known as HIF-2a, is a novel member of the PAS family that is closely related to HIF1a. EPAS1 is expressed at high levels in vascular endothelial cells, glomus cells in the Organ of Zuckerkrandl, and pulmonary pneumocytes of the developing mouse. Homozygous EPAS1 knockout 129 S6/SvEvTac mice die in mid-gestation, likely as a consequence of catecholamine insufficiency and/or vascular defects.
The expression of EPAS1 in the adult is more widespread in comparison to the developing embryo. The sites of expression of EPAS1 in the adult are in areas of high oxygen consumption (skeletal muscle, heart, liver) or in organs that are exquisitely responsive to hypoxia (carotid body, adrenal gland). We have recently found that the EPAS1 knockout allele is incompletely penetrant (i.e. embryonic lethal) on other genetic backgrounds. The surviving mice lacking EPAS1 exhibit pathology in multiple organs despite co-localization of other HIF members suggesting that HIF members are not functionally redundant. The phenotypic appearance resembles a mitochondrial disease state and the molecular etiology involves impaired oxidative stress response due to inadequate production of major antioxidant enzymes (AOE).
Other aspects of the EPAS1 null phenotype include a global defect in hematopoiesis. The molecular etiology for this involves inadequate production of the cytokine erythropoietin. These studies support a role for erythropoietin in early hematopoietic stem cell function. Other evidence that EPAS1 serves as a master regulator for erythropoietin comes from the reduced levels in the eye where erythropoietin plays a cytoprotective role. The retinopathy of EPAS1 null mice is multi-factorial and involves dysregulation of AOE, erythropoietin, and other as of yet unidentified factors.
Currently, we are continuing our studies on the physiologic role of EPAS1 in the adult mouse and on identifying the molecular targets for EPAS1. Our integrative experimental approach involves detailed surveys of histological and ultra-structural microarchitecture; molecular assays including RT-PCR, cDNA array, and biochemical analyses; and physiological studies including isolated organ as well as whole animal studies. Studies on EPAS1 will have important implications for human disease states involving hypoxic or other stress-induced injury.
RESEARCH INTERESTS
mouse models of human disease
stress signal transduction
HIF signaling
RECENT PUBLICATIONS
Oktay Y, Dioum E, Matsuzaki S, Ding K, Yan LJ, Haller RG, Szweda LI, Garcia JA., "Hypoxia-inducible factor 2{alpha} regulates expression of the mitochondrial aconitase chaperone protein frataxin." Journal of Biological Chemistry, 282/16:11750-6, February 2007
Ding K, Scortegagna M, Seaman R, Birch DG, and Garcia JA., "Retinal pathology in mice lacking the hypoxia inducible transcription factor HIF-2a." Invest Ophth Vis Sci, 46/3:1010-16, March 2005
Scortegagna M, Ding K, Zhang Q, Oktay Y, Bennett MJ, Bennett M, Shelton JM, Richardson JA, Moe O, Garcia JA., "HIF-2{alpha} regulates murine hematopoietic development in an erythropoietin-dependent manner." Blood, 105/8:3133-40, December 2004
M. Scortegagna, M.A. Morris, Y. Oktay, M. Bennett, and J.A. Garcia, "The HIF family member EPAS1/HIF-2a is required for normal hematopoiesis in mice" Blood, 102:1634-1640, September 2003
Scortegagna M, Ding K, Oktay Y, Gaur A, Thurmond F, Yan LJ, Marck BT, Matsumoto AM, Shelton JM, Richardson JA, Bennett MJ, Garcia JA., "Multiple organ pathology, metabolic abnormalities and impaired homeostasis of reactive oxygen species in Epas1-/- mice." Nature Genetics, 35/4:331-40, December 2003
SIGNIFICANT PUBLICATIONS
Scortegagna M, Ding K, Oktay Y, Gaur A, Thurmond F, Yan LJ, Marck BT, Matsumoto AM, Shelton JM, Richardson JA, Bennett MJ, Garcia JA., "Multiple organ pathology, metabolic abnormalities and impaired homeostasis of reactive oxygen species in Epas1-/- mice." Nature Genetics, 35/4:331-40, December 2003
Scortegagna M, Ding K, Zhang Q, Oktay Y, Bennett MJ, Bennett M, Shelton JM, Richardson JA, Moe O, Garcia JA., "HIF-2{alpha} regulates murine hematopoietic development in an erythropoietin-dependent manner." Blood, 105/8:3133-40, December 2004
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