(代po勿回) POST-DOCTORAL POSITION NATIONAL INSTITUTES OF HEALTHS – BETHESDA, MARYLAND, USA Janice Chou, Ph.D. Chief, Section on Cellular Differentiation PDEGEN, NICHD, NIH Building 10, Room 9D42, NIH 9000 Rockville Pike, Bethesda, Maryland 20892 Phone: 301-496-1094; Fax: 301-402-6035 Email: [email protected] Research Interests: Genetic diseases & gene therapy Endoplasmic reticulum stress & apoptosis Molecular Genetics of Heritable Human Disorders My laboratory conducts research to understand the molecular genetics and pathogenesis of human genetic disorders caused by a disturbance in glucose homeostasis. We focus on type I glycogen storage disease (GSD-I or von Gierke disease) that consists of GSD-Ia, deficient in the liver/kidney/ intestine-restricted glucose-6-phosphatase-α (G6Pase-α), and GSD-Ib, deficient in the ubiquitously expressed glucose-6-phosphate transporter (G6PT) (reviewed in 1). The G6Pase-α/G6PT complex is essential for maintenance of glucose homeostasis between meals and GSD-Ia and Ib patients manifest a phenotype of disturbed glucose homeostasis. GSD-Ib patients also suffer from myeloid dysfunctions of unknown etiology. We have isolated and characterized cDNAs and genes for G6Pase-α (2) and G6PT (3, 4), established the genetic basis of GSD-Ia (2) and GSD-Ib (4), and elucidated the mechanism of actions and topology of G6Pase-α (5, 6) and G6PT (7, 8). We also generated animal models of GSD-Ia (9) and GSD-Ib (10); both mimic the human diseases. Using these animal models, we have developed gene therapy for GSD-Ia and GSD-Ib (11, 12). More recently, we uncovered a ubiquitously expressed G6P hydrolase, G6Pase-β that shares kinetic, structural and active site similarities to G6Pase-α (13, 14) and couples functionally with the G6PT to form a G6Pase- /G6PT complex that can hydrolyze G6P to glucose. This implies that the myeloid defects in GSD-Ib arise from a non-productive interaction between a mutant G6PT and G6Pase-β. To address this we have generated a G6Pase-β-deficient mouse strain and shown that the knockout mice manifest myeloid dysfunctions mimicking GSD-Ib (15). We further show that neutrophils unable to produce endogenous glucose caused by a deficiency in either G6Pase-β or G6PT undergo ER stress and enhanced rate of apoptosis (15, 16). Current research focuses include: 1) develop somatic gene therapy for GSD-Ia using AAV vectors to achieve sustained, tissue-specific expression of the G6Pase-α gene and long-term correction of GSD-Ia.; (2) elucidate the etiology of long-term complication of GSD-Ia and GSD-Ib; 3) delineate the signaling pathways for ER stress and apoptosis in neutrophils and hematopoietic stem cells of GSD-Ib and G6Pase-β-deficient mice. --

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