Abstract: The present invention provides a mouse with liver damage, having a high degree of damage against the mouse's original hepatocytes while having a uPA gene in a heterozygous form, and a method for efficiently preparing the mouse. Specifically, the method for preparing a mouse with liver damage having the uPA gene in a heterozygous form comprises the following steps of: (i) transforming mouse ES cells with a DNA fragment containing a liver-specific promoter/enhancer and cDNA that encodes a urokinase-type plasminogen activator operably linked under the control thereof; (ii) injecting the transformed mouse ES cells obtained in step (i) into a host embryo; (iii) transplanting the host embryo obtained in step (ii) via the injection of the ES cells into the uterus of a surrogate mother mouse, so as to obtain a chimeric mouse; and (iv) crossing the chimeric mice obtained in step (iii), so as to obtain a transgenic mouse in which the DNA fragment is introduced in a heterozygous form.

Abstract: The present invention provides a mouse with liver damage, having a high degree of damage against the mouse's original hepatocytes while having a uPA gene in a heterozygous form, and a method for efficiently preparing the mouse. Specifically, the method for preparing a mouse with liver damage having the uPA gene in a heterozygous form comprises the following steps of: (i) transforming mouse ES cells with a DNA fragment containing a liver-specific promoter/enhancer and cDNA that encodes a urokinase-type plasminogen activator operably linked under the control thereof; (ii) injecting the transformed mouse ES cells obtained in step (i) into a host embryo; (iii) transplanting the host embryo obtained in step (ii) via the injection of the ES cells into the uterus of a surrogate mother mouse, so as to obtain a chimeric mouse; and (iv) crossing the chimeric mice obtained in step (iii), so as to obtain a transgenic mouse in which the DNA fragment is introduced in a heterozygous form.

Abstract: Provided is a non-human animal that is highly practical as a hyperuricenia model, the non-human animal being the following: (a) a non-human animal obtained by producing a primary chimeric non-human animal by transplantation of human hepatocytes to an immunodeficient non-human animal with liver dysfunction; and subsequently administering a purine base-containing substance to the primary chimeric non-human animal, or (b) a non-human animal obtained by producing a serially transplanted chimeric non-human animal via two steps, a first step being a step of producing a primary chimeric non-human animal by transplantation of human hepatocytes to an immunodeficient non-human animal with liver dysfunction, a second step being a step of transplanting the human hepatocytes grown in the body of the primary chimeric non-human animal to an immunodeficient non-human animal with liver dysfunction, the second step being performed one or more times; and subsequently administering a purine base-containing substance to the seri

Abstract: The present invention provides a mouse with liver damage, having a high degree of damage against the mouse's original hepatocytes while having a uPA gene in a heterozygous form, and a method for efficiently preparing the mouse. Specifically, the method for preparing a mouse with liver damage having the uPA gene in a heterozygous form comprises the following steps of: (i) transforming mouse ES cells with a DNA fragment containing a liver-specific promoter/enhancer and cDNA that encodes a urokinase-type plasminogen activator operably linked under the control thereof; (ii) injecting the transformed mouse ES cells obtained in step (i) into a host embryo; (iii) transplanting the host embryo obtained in step (ii) via the injection of the ES cells into the uterus of a surrogate mother mouse, so as to obtain a chimeric mouse; and (iv) crossing the chimeric mice obtained in step (iii), so as to obtain a transgenic mouse in which the DNA fragment is introduced in a heterozygous form.

Abstract: Provided is a non-human animal that is highly practical as a hyperuricenia model, the non-human animal being the following: (a) a non-human animal obtained by producing a primary chimeric non-human animal by transplantation of human hepatocytes to an immunodeficient non-human animal with liver dysfunction; and subsequently administering a purine base-containing substance to the primary chimeric non-human animal, or (b) a non-human animal obtained by producing a serially transplanted chimeric non-human animal via two steps, a first step being a step of producing a primary chimeric non-human animal by transplantation of human hepatocytes to an immunodeficient non-human animal with liver dysfunction, a second step being a step of transplanting the human hepatocytes grown in the body of the primary chimeric non-human animal to an immunodeficient non-human animal with liver dysfunction, the second step being performed one or more times; and subsequently administering a purine base-containing substance to the seri

Abstract: A chimeric non-human animal having an in vivo human hepatocyte population, wherein the effects of non-human animal cells on drug metabolism are suppressed or deleted is provided. A method for producing a chimeric non-human animal that lacks a drug-metabolizing system or has a suppressed drug-metabolizing system and is provided with a drug-metabolizing system driven by human hepatocytes, is provided. The method comprises transplanting human hepatocytes into a non-human animal characterized by (i) being immunodeficient, (ii) having liver damage, and (iii) lacking the functions of an endogenous Cyp3a gene.

Abstract: The present invention provides a mouse with liver damage, having a high degree of damage against the mouse's original hepatocytes while having a uPA gene in a heterozygous form, and a method for efficiently preparing the mouse. Specifically, the method for preparing a mouse with liver damage having the uPA gene in a heterozygous form comprises the following steps of: (i) transforming mouse ES cells with a DNA fragment containing a liver-specific promoter/enhancer and cDNA that encodes a urokinase-type plasminogen activator operably linked under the control thereof; (ii) injecting the transformed mouse ES cells obtained in step (i) into a host embryo; (iii) transplanting the host embryo obtained in step (ii) via the injection of the ES cells into the uterus of a surrogate mother mouse, so as to obtain a chimeric mouse; and (iv) crossing the chimeric mice obtained in step (iii), so as to obtain a transgenic mouse in which the DNA fragment is introduced in a heterozygous form.

Abstract: A chimeric non-human animal having an in vivo human hepatocyte population, wherein the effects of non-human animal cells on drug metabolism are suppressed or deleted is provided. A method for producing a chimeric non-human animal that lacks a drug-metabolizing system or has a suppressed drug-metabolizing system and is provided with a drug-metabolizing system driven by human hepatocytes, is provided. The method comprises transplanting human hepatocytes into a non-human animal characterized by (i) being immunodeficient, (ii) having liver damage, and (iii) lacking the functions of an endogenous Cyp3a gene.

Abstract: A polynucleotide encoding the amino acid shown in SEQ ID NO:2 or SEQ ID NO: 5, or encoding an amino acid sequence having not less than 98% identity thereto; preferably a polynucleotide comprising replacement of the amino acid corresponding to glutamic acid at position 1202 of SEQ ID NO:2 (position 177 of SEQ ID NO:5) with glycine, replacement of the amino acid corresponding to glutamic acid at position 1056 (position 31 of SEQ ID NO:5) with valine, and replacement of the amino acid corresponding to alanine at position 2199 (position 1174 of SEQ ID NO:5) with threonine.

Abstract: A polynucleotide encoding the amino acid shown in SEQ ID NO:2 or SEQ ID NO: 5, or encoding an amino acid sequence having not less than 98% identity thereto; preferably a polynucleotide comprising replacement of the amino acid corresponding to glutamic acid at position 1202 of SEQ ID NO:2 (position 177 of SEQ ID NO:5) with glycine, replacement of the amino acid corresponding to glutamic acid at position 1056 (position 31 of SEQ ID NO:5) with valine, and replacement of the amino acid corresponding to alanine at position 2199 (position 1174 of SEQ ID NO:5) with threonine.

Abstract: Disclosed is a nonhuman animal showing the symptoms of human nonalcoholic steatohepatitis which is obtained by transplanting human hepatocytes into an immunodeficient hepatopathic nonhuman animal to produce a chimeric nonhuman animal and then transplanting human hepatocytes that are propagated in the body of the chimeric nonhuman animal into an immunodeficient hepatopathic nonhuman animal of the same species as the immunodeficient hepatopathic nonhuman animal described above, as well as a nonhuman animal showing the symptoms of human fatty liver which is obtained by transplanting human hepatocytes into an immunodeficient hepatopathic nonhuman animal to produce a chimeric nonhuman animal.

Abstract: A polynucleotide encoding the amino acid shown in SEQ ID NO:2 or SEQ ID NO: 5, or encoding an amino acid sequence having not less than 98% identity thereto; preferably a polynucleotide comprising replacement of the amino acid corresponding to glutamic acid at position 1202 of SEQ ID NO:2 (position 177 of SEQ ID NO:5) with glycine, replacement of the amino acid corresponding to glutamic acid at position 1056 (position 31 of SEQ ID NO:5) with valine, and replacement of the amino acid corresponding to alanine at position 2199 (position 1174 of SEQ ID NO:5) with threonine.

Abstract: Human adult hepatocytes are transplanted into an immunodeficient hepatopathy mouse and then human growth hormone is administered to the mouse to thereby elevate twice or more the replacement ratio by the human adult hepatocytes having been transplanted. Further, human growth hormone is administered to an immunodeficient hepatopathy mouse carrying human young hepatocytes transplanted thereinto so as to improve fatty liver of the mouse in which about 70% or more of the hepatocytes have been replaced by the human hepatocytes.

Abstract: Disclosed is a nonhuman animal showing the symptoms of human nonalcoholic steatohepatitis which is obtained by transplanting human hepatocytes into an immunodeficient hepatopathic nonhuman animal to produce a chimeric nonhuman animal and then transplanting human hepatocytes that are propagated in the body of the chimeric nonhuman animal into an immunodeficient hepatopathic nonhuman animal of the same species as the immunodeficient hepatopathic nonhuman animal described above, as well as a nonhuman animal showing the symptoms of human fatty liver which is obtained by transplanting human hepatocytes into an immunodeficient hepatopathic nonhuman animal to produce a chimeric nonhuman animal.

Abstract: Transplanting human hepatocytes into a liver of an immunodeficient hepatopathy mouse, and then feeding the mouse transplanted with the human hepatocytes under such a condition as being protected from the attack by human complement produced by the human hepatocytes thereby proliferating the transplanted human hepatocytes in the mouse liver. Further, obtaining human hepatocytes in large scale by repeating the above steps using the proliferated human hepatocytes.

Abstract: Human adult hepatocytes are transplanted into an immunodeficient hepatopathy mouse and then human growth hormone is administered to the mouse to thereby elevate twice or more the replacement ratio by the human adult hepatocytes having been transplanted. Further, human growth hormone is administered to an immunodeficient hepatopathy mouse carrying human young hepatocytes transplanted thereinto so as to improve fatty liver of the mouse in which about 70% or more of the hepatocytes have been replaced by the human hepatocytes.

Abstract: It is intended to provide a method of screening a candidate drug mainly metabolized by a drug metabolizing enzyme, CYP2D6, CYP2C9 or CYP2C19 with the use of a chimeric mouse carrying human hepatocytes transplanted thereinto, whereby it is determined whether or not the candidate drug is metabolized in a subject deficient in CYP2D6, CYP2C9 or CYP2C19. It is also intended to provide a method of determining whether or not a candidate drug induces or inhibits the activity of any of drug metabolizing enzymes, CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 with the use of a chimeric mouse carrying human hepatocytes transplanted thereinto.

Abstract: The invention provides a monoclonal antibody which specifically recognizes proliferative human hepatocytes, a method for isolating proliferative human hepatocytes by using the antibody, and a method for inducing to differentiate the proliferative human hepatocytes to functional human hepatocytes. Further, the invention provides the proliferative human hepatocytes and functional human hepatocytes obtained by the methods, as well as a cell kit and a hybrid artificial liver comprising those hepatocytes.

Abstract: The invention provides a monoclonal antibody which specifically recognizes proliferative human hepatocytes, a method for isolating proliferative human hepatocytes by using the antibody, and a method for inducing to differentiate the proliferative human hepatocytes to functional human hepatocytes. Further, the invention provides the proliferative human hepatocytes and functional human hepatocytes obtained by the methods, as well as a cell kit and a hybrid artificial liver comprising those hepatocytes.

Abstract: Transplanting human hepatocytes into a liver of an immunodeficient hepatopathy mouse, and then feeding the mouse transplanted with the human hepatocytes under such a condition as being protected from the attack by human complement produced by the human hepatocytes thereby proliferating the transplanted human hepatocytes in the mouse liver. Further, Obtaining human hepatocytes in large scale by repeating the above steps using the proliferated human hepatocytes.