Stephanie Cherqui

RESEARCH

Islet transplantation is a promising treatment for insulin-dependent diabetes mellitus. The objective of my work is to test the use of lentiviral gene therapy to deliver a soluble factors that will be both proangiogenic and immunosuppressive to enhance transplant revascularization and preserve functional islet mass. The underlying premise of our research in tissue engineering and gene therapy is that the ability to enhance the revascularization of transplanted cells and control the implantation site, including the host immune response, will create a platform to advance the field.

The Specific Aims are:

1) Demonstrate that the co-transplantation of islets with endothelial cell progenitors or mature endothelial cells modified by ex vivo gene therapy with lentiviral vectors to deliver the proangiogenic and immunosuppressive factor will enhance islet revascularization and preserve functional islet mass and,

2) Demonstrate that co-transplantation of islets with host-derived endothelial cell progenitors or mature endothelial cells modified will protect both mouse allografts and pig islet xenografts from rejection in immune competent mice.

This strategy will be used to protect islets after transplantation and could even allow successful xenotransplantation, resolving two major challenges for islet transplantation: the death of transplanted islets within the first few weeks and the lack of available islets.

3) Advance our understanding of the cell signal pathways including growth factors, growth factor receptors, intracellular signaling and transcriptional regulators that determine the survival, proliferation and differentiation of endothelial progenitor cells during angiogenesis. These studies are using system biology tools such as gene expression profiling, tandem mass spectrometry proteomics and bioinformatics.

Our strategy is to integrate translational medicine with investigations of the cell biology of fundamental underlying mechanisms such as angiogenesis and progenitor cell development that ultimately determine the success of such interventions.

	Position: Research Associate Birthday: 20th September, 1975 Nationality: French Education: Ph.D. , University of René Descartes, Paris , France Email: scherqui@scripps.edu	Curriculum vitae

RESEARCH Islet transplantation is a promising treatment for insulin-dependent diabetes mellitus. The objective of my work is to test the use of lentiviral gene therapy to deliver a soluble factors that will be both proangiogenic and immunosuppressive to enhance transplant revascularization and preserve functional islet mass. The underlying premise of our research in tissue engineering and gene therapy is that the ability to enhance the revascularization of transplanted cells and control the implantation site, including the host immune response, will create a platform to advance the field. The Specific Aims are: 1) Demonstrate that the co-transplantation of islets with endothelial cell progenitors or mature endothelial cells modified by ex vivo gene therapy with lentiviral vectors to deliver the proangiogenic and immunosuppressive factor will enhance islet revascularization and preserve functional islet mass and, 2) Demonstrate that co-transplantation of islets with host-derived endothelial cell progenitors or mature endothelial cells modified will protect both mouse allografts and pig islet xenografts from rejection in immune competent mice. This strategy will be used to protect islets after transplantation and could even allow successful xenotransplantation, resolving two major challenges for islet transplantation: the death of transplanted islets within the first few weeks and the lack of available islets. 3) Advance our understanding of the cell signal pathways including growth factors, growth factor receptors, intracellular signaling and transcriptional regulators that determine the survival, proliferation and differentiation of endothelial progenitor cells during angiogenesis. These studies are using system biology tools such as gene expression profiling, tandem mass spectrometry proteomics and bioinformatics. Our strategy is to integrate translational medicine with investigations of the cell biology of fundamental underlying mechanisms such as angiogenesis and progenitor cell development that ultimately determine the success of such interventions.

PUBLICATIONS Kalatzis V, Cherqui S , Nevo N, Gasnier B, Antignac C. ( 2004 ). Molecular pathogenesis of cystinosis: effect of CTNS mutations on the transport activity and subcellular localization of cystinosin. *Hum Mol Genet* . 13(13):1361-1371. Cherqui S , Sevin C., Hamard G., Kalatzis V., Sich M., Pequignot M.O., Gogat K., Abitbol M., Broyer M., Gubler M.C. and Antignac C. ( 2002 ). Intra-lysosomal cystine accumulation in mice lacking cystinosin, the protein defective in cystinosis. *Mol Cell Biol* . 22(21): 7622-7632. Kalatzis V, Cherqui S , Antignac C, Gasnier B. ( 2001 ) Cystinosin, the protein defective in cystinosis, is a H + -driven lysosomal cystine transporter. *EMBO J* . 20(21): 5940-5949. Kalatzis V, Cherqui S , Jean G, Cordier B, Broyer M, Cochat P, Antignac C. ( 2001 ) Characterisation of a putative founder mutation accounts for high incidence of cystinosis in Brittany . *J Am Soc Nephrol* 12(10): 2170-2174. Cherqui S , Kalatzis V, Trugnan G, Antignac C. ( 2001 ) The targetting of cystinosin to the lysosomal membrane requires a tyrosine-based signal and a novel sorting motif. *J Biol Chem* . 276: 13314-13321. Cherqui S , Kalatzis V, Forestier L, Poras I, Antignac C. ( 2000 ) Identification and Characterisation of the Murine Homologue of the Gene Responsible for Cystinosis, Ctns . *BMC Genomics* . 1(1):2. Attard M, Jean G, Forestier L, Cherqui S , van't Hoff W, Broyer M, Antignac C, Town M. ( 1999 ) Severity of phenotype in cystinosis varies with mutations in the CTNS gene: predicted effect on the model of cystinosin. *Hum Mol Genet* . 8(13): 2507-2514. Forestier L, Jean G, Attard M, Cherqui S , Lewis C, van't Hoff W, Broyer M, Town M, Antignac C. ( 1999 ) Molecular characterization of CTNS deletions in nephropathic cystinosis: development of a PCR-based detection assay. *Am J* Hum Genet . 65(2): 353-359. Town M, Jean G, Cherqui S , Attard M, Forestier L, Whitmore SA, Callen DF, Gribouval O, Broyer M, Bates GP, van't Hoff W, Antignac C. ( 1998 ) A novel gene encoding an integral membrane protein is mutated in nephropathic cystinosis. *Nature Genet* . 18(4): 319-324.