|
Oregon Health & Science Univ
Molecular & Medical Genetics
Mail Code: L103
3181 SW Sam Jackson
Park Road
Portland, OR 97239
503-494-7703
|
|
|
|  |
Markus Grompe, M.D. - Professor
Oregon Health & Science University
3181 SW Sam Jackson Park Road
Mail Code L321
Portland, OR 97239
E-Mail: grompem@ohsu.edu
|
RESEARCH
Single gene disorders, although individually rare, cumulatively represent a significant medical burden, particularly in the pediatric age group. Current treatment options are very limited and outcomes remain poor in many cases. Gene transfer and cell therapy (including stem cell transplantation) are hopeful strategies for future therapies. It is our long-term goal to develop these into clinically useful procedures. Our particular focus is metabolic liver diseases and the DNA repair disease Fanconi Anemia.
METABOLIC LIVER DISEASE AND THERAPY
The level of cell replacement required to achieve physiological benefit in the treatment of genetic liver disorders depends on which disease is being treated.The threshold can be as low as only 1% in the hemophilias or as high as 50% in urea cycle disorders. Even the low threshold is difficult to achieve with cell therapy or integrating gene transfer vectors required for life-long therapy. Fortunately, the liver is a highly regenerative organ and in mutant backgrounds where genetically normal hepatocytes have a selective advantage, extensive repopulation can be achieved. We first showed in fumaryl acetoacetate hydrolase (Fah) deficient mice that cell replacement levels can reach levels of >98% illustrating the concept of "therapeutic liver repopulation" (Overturf et al. 1996). We are using liver repopulation as an assay for the discovery and purification of hepatocyte progenitors from liver (intrahepatic stem cells), pancreas (hepatopancreatic stem cell) and bone marrow (bone marrow derived hepatocytes). Cell surface markers for the prospective isolation of these cell types are being developed. In addition, we are working out protocols for hepatic conditioning, which will permit selective expansion of transplanted cells in any setting.
FANCONI ANEMIA AND INTERSTRANDCROSS-LINKS
Fanconi anemia (FA) is a genetic disorder that affects multiple stem cell stypes, particularly hematopoietic stem cells and germline stem cells. Clinically, it is characterized by birth defects, progressive bone marrow failure and/or leukemia. FA cells are hypersensitive to DNA cross-linking agents and have an abnormal cell cycle. At least 11 different FA complementation groups (A, B, C, D1, D2, E, F, G, I, J and L) exist and the corresponding genes for 9 of these have been cloned. Importantly, the gene mutated in FA groups B and D1 is BRCA2, the breast cancer susceptibility gene. The biochemical function(s) of the pathway are unknown. This laboratory is interested in the basic defect in FA cells and therapeutic approaches. Wild-type hematopoieticstem cells have a marked selective growth advantage in FA, marking this disorder an ideal system to explore new strategies for gene therapy in blood stem cells.
SELECT PUBLICATIONS
X. Wang, H. Willenbring, Y. Akkari, Y. Torimaru, M. Foster, M. Al-Dhalimy, E. Lagasse, M. Finegold, S. Olson and M. Grompe (2003) "Cell fusion is the principal source of bone-marrow derived hepatocytes", Nature 422(6934):897-901
X. Wang, M. Foster, M. Al-Dhalimy, E. Lagasse, M. Finegold and M. Grompe (2003) "The origin and liver repopulating capacity of murine oval cells", Proceedings of the National Academy of Sciences USA, 100 Suppl. 1: 11881-8
H. Willenbring, A. S. Bailey, M. Foster, Y, Akkari, C. Dorrell, S. Olson, M. Finegold, W. H. Fleming and M. Grompe (2004) "Myelomonocytic cells are sufficient for therapeutic cell fusion in liver", Nature Medicine 10(7):744-8
S. Houghtaling, C. Timmers, M. Noll, S.N. Jones, M. Finegold, S. Meyn and M. Grompe (2003) "Epithelial cancers in Fanconi Anemia D2 (Fancd2) knockout mice", Genes & Development, 7(16):2021-3
A. Rothfuss and M. Grompe (2004) "Repair Kinetics of Genomic Interstrand DNA Cross-Links: Evidence for DNA Double-Strand Break-Dependent Activation of the Fanconi Anemia / BRCA pathway", Molecular and Cellular Biology 24(1): 123-34
For more information on publications, contact the faculty member or search PubMed.
GRADUATE PROGRAM AFFILIATIONS: |
|
|
|
