Transgenic Mouse as a Tool in Human Genetics.
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概要
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Transgenic mice have been used for analyses of cis-acting elements which is involved in the tissue-specific and developmental-specific expression, for analyses of physiological function of genes, or for the production of human disease model. This approach is especially successful in the field of Genetics and Immunology. For the past several years we have been studying one of human genetic diseases, Familial amyloidotic polyneuropathy (FAP) . FAP is one type of systemic amyloidosis and is an autosomal dominant disorder characterized by the extracellular deposition of amyloid fibrils and by prominent peripheral and autonomic nerve involvement. Accumulating evidences suggest that the main cause of this disease is the presence of the mutant transthyretin (TTR) gene. However, many questions in relation to the disease process remain to be elucidated. In addition, there is no effective therapy for FAP. To elucidate the pathological process of this disease development and to devise a new method for treatment, we have produced a transgenic mouse model of FAP by introducing the human mutant transthyretin (hMet30) gene. In these transgenic mice, amyloid deposition starts to occur at around 6 months of age and the amount of amyloid deposition increases gradually with aging. Amyloid deposition is observed in many tissues including heart, kidney and thyroid gland, where amyloid deposition is commonly observed in FAP patient. There was a big variation at the age of onset although we used an inbred strain of mouse, C57BL/6, in these experiments and the serum concentrations of hMet30 were about the same in these transgenic mice. The hMet30 gene was found to be expressed from fetal stage. These results suggest that amyloid deposition itself starts to occur late in life and that this amyloid deposition is influenced by environmental factors.<BR>Several years ago we showed that the major histocompatibility complex (MHC) class II gene is identical to the immune response gene by demonstrating that the immune response can be restored by the new expression of class II molecules on immunocompetent cells. Recent evidence suggest that class II molecule is involved in the generation of autoimmune disease, such as insulin dependent diabetes mellitus (IDDM) . NOD (non-obese diabetic) mouse is shown to be a mouse model for human IDDM. Concerning the class II genes, NOD mouse has two characteristic features, the lack of I-E and the presence of unique I-A. In order to examine the role of these class II molecules, we produced NOD transgenic mice by introducing murine class II genes. The incidences of insulitis in I-E and I-A transgenic mice were much lower than that of control NOD mice suggesting that both the lack of I-E and the presence of unique I-A are responsible for the development of insulitis in NOD mouse. Our data also suggest that the amino acid at position 57 of A<SUP>β</SUP> chain is not the only cause for insulitis.<BR>Recent technical advance in gene targeting together with the conventional transgenic tecnnique will be a powerful tool not only for the establishment of a transgenic mouse model for the human disease but also for analyses of disease process of human disease.
- 公益社団法人 日本実験動物学会の論文
公益社団法人 日本実験動物学会 | 論文
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