POST-DOCTORAL POSITION – NATIONAL INSTITUTES OF HEALTHS – BETHESDA, MARYLAND, USA POST-DOCTORAL RESEARCH POSITION is available to study the molecular genetics and pathogenesis of heritable metabolic human disorders. The project will involve mouse models of genetic disease to increase our basic understanding of the biology and pathophysiology of the disorders and to develop somatic gene therapies. The project will utilize biochemical, cellular, molecular, and immunological techniques. We are looking for a highly motivated individual with a Ph.D. and/or M.D. with interests in the area of molecular genetics. Strong background in molecular biology and/or protein biochemistry is desirable. The position will be available in January 2004. Salary is highly competitive and will depend on the qualifications of the candidate. The period of initial appointment is two years but may be extended for additional three years. Qualified and interested candidates should send a copy of their curriculum vitae, bibliography, and contact details including phone number and email address of three referees to: Janice Chou, Ph.D., Section on Cellular Differentiation, Heritable Disorders Branch, NICHD, NIH, 9000 Rockville Pike, Bethesda, Maryland 20892-1830, USA. Phone 301-496-1094; Fax 301-402-6035; Email [email protected] Or for information, please contact Dr. Hungwen Chen, Institute of Biological Chemistry, Academia Sinica, Taiwan. Phone 02-27855696 ext 6090; Email [email protected] POST-DOCTORAL POSITION – NATIONAL INSTITUTES OF HEALTHS – BETHESDA, MARYLAND, USA Janice Chou, Ph.D. Chief, Section on Cellular Differentiation Heritable Disorders Branch, NICHD, NIH Building 10 / Room 9S241, NIH 9000 Rockville Pike Bethesda, Maryland 20892 Phone: 301-496-1094; Fax: 301-402-6035 Email: [email protected] Research Interests: Genetic Diseases & Gene Therapy Genetics and Human Genome Molecular & Cellular Biology Molecular Genetics of Heritable Human Disorders Current research focused on understanding the molecular and pathophysiological bases of the heritable type I glycogen storage disease (GSD-I), also known as von Gierke disease. GSD-I is a group of autosomal recessive disorders caused by a deficiency in the endoplasmic reticulum (ER)-bound glucose-6-phosphatase (G6Pase) complex that consists of G6Pase and glucose-6-phosphate transporter (G6PT). G6PT translocates G6P from cytoplasm to the lumen of the ER where G6Pase metabolizes G6P to glucose and phosphate. Together, G6Pase and G6PT maintain glucose homeostasis. Deficiencies in G6Pase cause GSD-1a and deficiencies in G6PT cause GSD-1b. Both manifest phenotypic G6Pase deficiency characterized by growth retardation, hypoglycemia, hepatomegaly, kidney enlargement, hyperlipidemia, hyperuricemia, and lactic acidemia. GSD-Ib patients also suffer from neutropenia and myeloid dysfunctions. My laboratory isolated and characterized cDNAs and genes for G6Pase and G6PT, developed gene-based diagnosis for both disorders, established the genetic bases of GSD-Ia and GSD-Ib. Furthermore, we elucidated the mechanism of actions of G6Pase as well as G6PT, the topology of both proteins in the membrane, the nature of the active site of G6Pase, and the regulatory elements of the human G6Pase and G6PT genes. We also generated G6Pase knockout mice that mimic the pathophysiology of human GSD-Ia and G6PT knockout mice that mimic the pathophysiology of human GSD-Ib. Using the GSD-Ia mice, we developed an adeno-associated virus vector-mediated gene therapy that corrected the murine disease for at least 12 months. My current areas of GSD-I research include: (1) delineating the relationship between G6Pase over-expression and diabetes; (2) elucidating the biology and pathogenesis of GSD-Ia; and (3) delineating the structure-function relationship of G6Pase and G6PT; (4) elucidating the biology and pathogenesis of GSD-Ib; and (5) developing somatic gene therapy for GSD-Ib using the G6PT-deficient mouse model. Selected Journal Publications 1. Lei K-J, Shelly LL, Pan C-J, Sidbury JB, Chou JY (1993) Mutations in the glucose-6-phosphatase gene that cause glycogen storage disease type 1a. Science 262:580-583 2. Lei K-J, Chen H, Pan C-J, Ward JM, Mosinger B, Lee EJ, Westphal H, Mansfield BC, Chou JY (1996) Glucose-6-phosphatase dependent substrate transport in the glycogen storage disease type 1a mouse. Nature Genetics 13:203-209 3. Pan C-J, Lei K-J, Annabi B, Hemrika W, Chou JY (1998) Transmembrane topology of glucose-6-phosphatase. J Biol Chem 273:6144-6148 4. Hiraiwa H, Pan C-J, Lin B, Moses, SW, Chou JY (1999) Inactivation of the glucose-6-phosphate transporter causes glycogen storage disease type 1b. J Biol Chem 274:5532-5536 5. Chou, JY, Mansfield BC (1999) Molecular genetics of type 1 glycogen storage diseases. Trend Endocrinol Metab 10:104-113 6. Chen L-Y, Lin B, Pan C-J, Hiraiwa H, Chou JY (2000) Structural requirements for the stability and microsomal transport activity of the human glucose-6-phosphate transporter. J Biol Chem 275:34280-34286 7. Shieh J-J, TerzioElu M, Hiraiwa H, Marsh J, Pan C-J, Chen L-Y, Chou JY (2001) The molecular basis of glycogen storage disease type 1a: structure and function analysis of mutations in glucose-6-phosphatase. J Biol Chem 277:5047-5053 8. Sun M-S, Pan C-J, Shieh J-J, Ghosh A, Chen L-Y, Mansfield BC, Ward JM, Byrne BJ, Chou JY (2002) Sustained hepatic and renal glucose-6-phosphatase expression corrects glycogen storage disease type Ia in mice. Hum Mol Genet 11:2155-2164 9. Chen L-Y, Pan C-J, Shieh J-J, Chou JY (2002) Structure-function analysis of the glucose-6-phosphate transporter deficient in glycogen storage disease type Ib. Hum Mol Genet 11:3199-3207. 10. Ghosh A, Shieh J-J, Pan C-J, Sun M-S, Chou JY (2002) The catalytic center of glucose-phosphatase: His176 is the nucleophile forming the phosphohistidine-enzyme intermediate during catalysis. J Biol Chem 277:32837-32842 11. Chou JY, Matern D, Mansfield BC, Chen Y-T (2002) Type I glycogen storage diseases: disorders of the glucose-6-phosphatase complex. Curr Mol Med 2:121-143 --

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