An animal model of Gaucher disease could be of great value in studying treatment strategies and some features of the pathogenesis of the disease. However, attempts to create such a model have been unsuccessful. The knockout mouse proved to be lethal at about the time of birth. We have now created a murine model of Gaucher disease by creating a chimeric mouse, transplanting wildtype mice with liver-derived hematopoietic stem cells from knockout fetuses. The peripheral blood and spleen from these animals is deficient in glucocerebrosidase activity and the amount of glucocerebroside in the liver and spleen is increased. Moreover, intravenous loading of the animals with glucocerebroside/albumin given intravenously increases the glucocerebroside levels further. We propose to further exploit this model by studying the natural history of glucocerebroside accumulation and by attempting to load these animals in a more convenient and possibly more physiologic manner. Such loading techniques might consist of intraperitoneal injection of glucocerebroside or the increase of blood cell turnover by the administration of G-CSF or phenylhydrazine. A """"""""readout"""""""" that is more facile than chemical determination of glucocerebroside by HPLC will also be explored. In particular, electron microscopy and light microscopy will be used to attempt to demonstrate the development of Gaucher cells in the chimeric mice.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK061370-02
Application #
6724900
Study Section
Medical Biochemistry Study Section (MEDB)
Program Officer
Mckeon, Catherine T
Project Start
2003-04-01
Project End
2006-01-31
Budget Start
2004-02-01
Budget End
2005-01-31
Support Year
2
Fiscal Year
2004
Total Cost
$187,700
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Beutler, Ernest (2006) Gaucher disease: multiple lessons from a single gene disorder. Acta Paediatr Suppl 95:103-9
Beutler, Ernest (2006) Lysosomal storage diseases: natural history and ethical and economic aspects. Mol Genet Metab 88:208-15
Beutler, Ernest; Gelbart, Terri; Scott, C Ronald (2005) Hematologically important mutations: Gaucher disease. Blood Cells Mol Dis 35:355-64
Efferth, Thomas; Bachli, Esther B; Schwarzl, Sonja M et al. (2004) Glucose-6-phosphate dehydrogenase (G6PD) deficiency-type Zurich: a splice site mutation as an uncommon mechanism producing enzyme deficiency. Blood 104:2608
Beutler, Ernest; Beutler, Lisa; West, Carol (2004) Mutations in the gene encoding cytosolic beta-glucosidase in Gaucher disease. J Lab Clin Med 144:65-8