徵博士後研究員 - 生技

(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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