H-PGDS (Biochem. Biophys. Acta 575:43–51, 1979; J. Biol. Chem. 262:3820–3825, 1987; Cell 90;1085–1095, 1997) is an enzyme having the function of producing an endogenous substance, prostaglandin D2 (PGD2: Prostaglandins Leukot. Essent. Fatty Acids, 37:219–234, 1989; FASEB J. 5:2575–2581, 1991; J. Lipid Mediat. Cell Signaling, 14:71–82, 1996) that has various physiological activities, and it is expressed in immunocytes and genital organs (J. Immunol. 143:2982–2989, 1989; J. biol. Chem. 270:3239–3246, 1995). It is known that PGD2 produced from mast cells by the action of H-PADS is involved in excacerbation of inflammations, and its degraded substance, 15d-PGJ2 (15-deoxy-Δ12,14-PGJ2) is a differentiation factor for adipose cell (Cell, 83:803–812 & 813–819, 1995).
H-PGDS is expressed in mast cell and antigen-presenting cell J. Immunol. 143:2982–2989, 1989; J. Biol. Chem. 270:3239–3246, 1995), and participates in production of PGD2 in allergic inflammation. It is known that thus produced PGD2 causes bronchoconstriction and vasodilation and involves in ingravescence of allergies.
Of all endogenous sleep-inducing substances that have been clarified up to the present, PGD2 has the most potent sleep-inducing activity. It is reported that in human patients suffering from trypanosome-infected African sleeping sickness, the PGD2 level in the cerebrospinal fluid increases 100 to 1,000-fold with ingravescence of the disease condition (Trans Royal Soc. Trop. Med. Hyg. 84:795–799, 1990). In addition, it is known that in pathologic deep sleep observed in systemic mastocytosis patients, the blood PGD2 level also increases 150-fold (New Engl. J. Med. 303:1400–1404, 1980), and the important role of PGD2 in pathologic sleep is suggested.
As mentioned above, it is suggested that PGD2 and H-PGDS producing PGD2 closely correlate to various physiological functions of individuals, and may be a potential cause of human diseases. However, no animal model system has as yet been established that enables the study under the controlled condition how the over expression of H-PGDS will act on animal.
The invention of this application has been made in consideration of the above-mentioned situation, and its object is to provide a non-human animal that genetically expresses a large amount of H-PGDS. Another object of this application is to provide methods of using the animal for testing the effectiveness of preventing or curing substances for various diseases caused by the over expression of H-PGDS in the animal.
USPTO Backgrounds
USPTO Backgrounds