- Mice carrying the tight skin mutation (Tsk) have thickened skin and visceral fibrosis. The accumulation of extensive genetic analysis in the principal investigator's laboratory resulted in the recent demonstration of a mutation in the fibrillin gene (fbn-1). This mutation causes an in- frame duplication of a region of the gene and results in the expression of a larger fibrillin molecule (450 v 330 kDa). The larger fibrillin protein is secreted into the extracellular matrix in an amount approximately equal to that of the normal protein. In collaboration with Dr. Kielty the principal investigator has demonstrated that the increased size of fibrillin is seen as an increase in intersubunit distance in fibrillin isolated from tissue of Tsk mice. It might be expected that the increased collagen deposition in these mice occurs in response to altered mechanical properties of the matrix resulting from a disruption in components of the elastin-associated matrix. However the principal investigator has some evidence that collagen synthesis is increased in fibroblasts isolated from embryos homozygous for the mutation and to a lesser extent in fibroblasts from embryos heterozygous for the mutation. The principal investigator hypothesizes that the duplication seen in this gene is responsible for the increased collagen synthesis and has focused on two elements of the gene that are duplicated, a putative TGF-binding domain and an RGD sequence.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
2R01AR032564-13A1
Application #
2691088
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1988-04-01
Project End
2003-06-30
Budget Start
1998-07-20
Budget End
1999-06-30
Support Year
13
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Thomas Jefferson University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
061197161
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Christner, Paul J; Jimenez, Sergio A (2004) Animal models of systemic sclerosis: insights into systemic sclerosis pathogenesis and potential therapeutic approaches. Curr Opin Rheumatol 16:746-52
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Gayraud, B; Keene, D R; Sakai, L Y et al. (2000) New insights into the assembly of extracellular microfibrils from the analysis of the fibrillin 1 mutation in the tight skin mouse. J Cell Biol 150:667-80
Christner, P J; Artlett, C M; Conway, R F et al. (2000) Increased numbers of microchimeric cells of fetal origin are associated with dermal fibrosis in mice following injection of vinyl chloride. Arthritis Rheum 43:2598-605
Siracusa, L D; McGrath, R; Fisher, J K et al. (1998) The mouse tight skin (Tsk) phenotype is not dependent on the presence of mature T and B lymphocytes. Mamm Genome 9:907-9
Kielty, C M; Raghunath, M; Siracusa, L D et al. (1998) The Tight skin mouse: demonstration of mutant fibrillin-1 production and assembly into abnormal microfibrils. J Cell Biol 140:1159-66
Siracusa, L D; McGrath, R; Ma, Q et al. (1996) A tandem duplication within the fibrillin 1 gene is associated with the mouse tight skin mutation. Genome Res 6:300-13
Christner, P J; Peters, J; Hawkins, D et al. (1995) The tight skin 2 mouse. An animal model of scleroderma displaying cutaneous fibrosis and mononuclear cell infiltration. Arthritis Rheum 38:1791-8
Jimenez, S A; Christner, P (1994) Animal models of systemic sclerosis. Clin Dermatol 12:425-36
Goldstein, C; Liaw, P; Jimenez, S A et al. (1994) Of mice and Marfan: genetic linkage analyses of the fibrillin genes, Fbn1 and Fbn2, in the mouse genome. Mamm Genome 5:696-700

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