Multicellular living organisms and unmodified parts thereof and – Nonhuman animal
Patent
1995-04-24
1998-05-12
Chambers, Jasemine C.
Multicellular living organisms and unmodified parts thereof and
Nonhuman animal
800DIG1, 800DIG2, 800DIG3, 4351723, 435325, 4353201, 935 53, 935 70, C12N 500, C12N 1500, C12N 1509
Patent
active
057508259
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of International Application Serial No. PCT/JP93/01522 filed on Oct. 21, 1993 which claims priority to the Japanese Application Serial No. 4-286131 filed on Oct. 23, 1992.
TECHNICAL FIELD
The present invention relates to a heretofore undocumented novel animal strain and to a method for producing it.
The animal of the present invention is a mouse for experimentation and research, a portion of whose endotheline-1 structural gene has a mutation. The peptide synthesis therefrom is suppressed as a result. This characteristic renders it extremely useful as an experimental animal for research toward elucidation of the pathological physiology and causes of and development of therapies for cardiovascular diseases such as hypertension, arteriosclerosis and ischemic heart disease.
BACKGROUND ART
A number of cardiovascular-active substances are receiving attention for their role in the pathological physiology of cardiovascular diseases such as hypertension, arteriosclerosis and ischemic heart disease. One of these, endotheline, is a 21-amino acid vasoconstrictor peptide isolated and purified from cardiovascular endothelial cells, and its nature was elucidated in 1988 (Yanagisawa, M., Kurihara, H., Kimura, S. et al. Nature 332:411, 1988).
The histological distribution of endotheline is so wide as to include the heart, kidney, adrenal, lungs, brain, etc. Its activity sites are also as varied as its histological distribution, including smooth muscle, vascular endothelium, cardiac muscle, the kidney, adrenal, central nervous system, etc. Attempts to delineate the physiological function of endotheline have been made by way of pharmacological tests, biochemical analyses and clinical research, but as yet the nature thereof has not been ascertained. Furthermore, there has not been available a mouse with defective endotheline gene function which is necessary for elucidation of the physiological function thereof.
In light of these circumstances, the present inventors have prepared a mouse lacking the gene for a cardiovascular-active substance and analyzed the resulting changes in physiological function including hemodynamics, thus allowing direct understanding of the physiological role of the cardiovascular-active substance while also providing an animal model with a well-defined genetic background for research toward the pathological elucidation of and methods of therapy for cardiovascular diseases.
DISCLOSURE OF THE INVENTION
Consequently, the present invention provides a mouse which has been genetically engineered to artificially lack the endotheline-1 gene (ET-1 gene) function.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows the structure of the mouse genomic ET-1 gene fragment. The Roman numerals I to V in FIG. 1 indicate exon Nos. 1 to 5.
FIG. 2 shows the gene of FIG. 1 after insertion of a neomycin-resistance gene (neo.sup.r) into exon No. 2 and a thymidine kinase gene (HSV-tk) downstream from exon No. 5.
DETAILED DESCRIPTION OF THE INVENTION
In order to obtain a mouse artificially lacking the endotheline-1 gene function, there was employed a method by which the endotheline-1 gene was cloned, inactivated in vitro by some method and then returned to the mouse. The cloning of the endotheline-1 gene may be carried out by, for example, extracting genomic DNA from mouse liver, preparing a DNA library in the conventional manner, and then screening DNA, for example, cDNA (See Yanagisawa, M., Kurihara, H., Kimura, S. et al. Nature 332:411, 1988) coding for endotheline-1 which has already been cloned therefrom.
As shown in FIG. 1, the gene for the endotheline-1 precursor contains the 5 exons I to V, and endotheline-1 itself is encoded by exon No. 2. The function of the endotheline-1 gene may be rendered defective either by deleting one of the portions of the gene coding for the endotheline-1 precursor (hereunder referred to simply as "endotheline-1 gene") or by inserting another gene at one of the sites; however, it is preferable to insert another gene which also functions as a genetic mark
REFERENCES:
patent: 5416260 (1995-05-01), Koller et al.
Bradley et al., BioTechnology 10:534-539 (1992).
Yanagisawa et al., Nature 332: 411-415 (1988).
Blaine et al., "Clinical and Therapeutic Implications of New Peptides in Hypertension", Current Opinion in Cardiology, vol. 6, No. 5, (1991), pp. 686-692.
Kodama Tatsuhiko
Kurihara Hiroki
Kurihara Yukiko
Suzuki Hiroshi
Yazaki Yoshio
Chambers Jasemine C.
Chugai Seiyaku Kabushiki Kaisha
Schmuck Jill D.
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