(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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