Abstract: A transgenic mouse having somatic and germ cells in which at least one allele of an endogenous interleukin-1.beta. converting enzyme (ICE) gene is functionally disrupted is provided. The mouse may be heterozygous or, more preferably, homozygous for the ICE gene disruption. In homozygous mice, secretion of mature interleukin-1.beta. and interleukin-1.alpha. is substantially reduced relative to non-mutant mice. The mice of the invention can be used as positive controls to evaluate the efficacy of ICE inhibitors and to identify disease conditions that can be treated with ICE inhibitors. A transgenic mouse having functionally disrupted endogenous ICE genes but which has been reconstituted with a human ICE gene is also provided. This mouse can be used to identify agents that inhibit human ICE in vivo.

Abstract: The non-coding regulatory sequences of the prostate specific antigen (PSA) are described. Non-human transgenic animals are also provided which express human PSA, which is non-naturally occurring in non-human animals.

Abstract: The present invention is directed to mice which are genetically altered to be deficient in the normal expression of RXR.gamma., to mice heterozygous for such deficiency, and to cell lines, preferably pluripotent or totipotent cell lines, which are heterozygous or homozygous for such deficiency. The invention further provides mice and cell lines which, in addition to being deficient in RXR.gamma., are genetically altered to be deficient in the expression of RXR.alpha. and/or RXR.beta.. The present invention further provides the use of any of the above mice and cell lines in situations where the absence of RXR.gamma., or the normal expression thereof, is desirable.

Abstract: A method to produce a cell expressing an antibody from a genomic sequence of the cell comprising a modified immunoglobulin locus using Cre-mediated site-specific recombination is disclosed. The method involves first transfecting an antibody-producing cell with a homology-targeting vector comprising a lox site and a targeting sequence homologous to a first DNA sequence adjacent to the region of the immunoglobulin loci of the genomic sequence which is to be converted to a modified region, so the first lox site is inserted into the genomic sequence via site-specific homologous recombination. Then the cell is transfected with a lox-targeting vector comprising a second lox site suitable for Cre-mediated recombination with the integrated lox site and a modifying sequence to convert the region of the immunoglobulin loci to the modified region.

Abstract: Transgenically modified animals which replicate hepatitis viruses are provided for use in evaluating virus-chemical and virus-drug interactions in chronic hepatitis infections.

Abstract: Disclosed is a mouse in which expression of the gene encoding Osteoprotegerin is suppressed. Also disclosed is a nucleic acid construct useful in preparing such a mouse, and a cell line containing such construct.

Abstract: The present invention provides mouse models of growth hormone insensitivity including Laron syndrome. In particular, the present invention provides transgenic mice incapable of expressing functional growth hormone receptor including mice which further cannot express functional growth hormone binding protein. The invention further provides methods for testing the usefulness of chemical compounds in the treatment of growth hormone insensitivity and diabetic end-organ disease.

Abstract: Transgenic mice with a non-functional proteinase activated receptor-2 (PAR2) gene are prepared by targeted disruption of the endogenous PAR2 gene. The resulting transgenic mice display a phenotype including a lack of a hypotensive response to administration of the peptide, SLIGRL, and a reduction in carrageenin-induced paw edema compared to wild type mice.

Abstract: Antibodies with fully human variable regions against a specific antigen can be prepared by administering the antigen to a transgenic animal which has been modified to produce such antibodies in response to antigenic challenge, but whose endogenous loci have been disabled. Various subsequent manipulations can be performed to obtain either antibodies per se or analogs thereof.

Abstract: The present invention provides a vector system that is useful for the generation of mutations in a recombination-based construction method. The invention further includes the incorporation of mutations generated by the method of the present invention into mouse embryonic stem cells and transgenic mice.

Abstract: A monoclonal preparation of lymphocytes, their production and use.

Abstract: The present invention discloses MmRad51-deficient transgenic mice and mouse cells, as well as MmRad51/p53-deficient transgenic mice and mouse cells. Also described is a method of screening for proteins that rescue the senescence phenotype in MmRad51/p53-deficient cells.

Abstract: Novel transgenic nonhuman animals, such as transgenic mice, for detecting and characterizing mutations in vivo are disclosed. When detecting reverse mutations, such as mutations of the APRT gene, the transgenic nonhuman animal now afford the unique advantage of detecting and characterizing mutations in vivo without having to sacrifice the animals as required heretofore. Moreover, since the transgenic nonhuman animals do not need to be sacrificed, they provide the unique opportunity to correlate the incidence and location of tumors (carcinogenesis) with the incidence and location of mutagenesis. Also disclosed are novel constructs, cell lines and chimeric animals for producing the novel transgenic animals. Novel methods for detecting and characterizing the mutations in vivo and producing animals for use in accordance with the methods of the instant invention are disclosed.

Abstract: The present invention provides mice which are deficient in the normal expression of one or more members of the RAR or RXR class of receptors, mice which are heterozygous for such deficiency, and to cell lines, preferably pluripotent or totipotent cell lines, which are heterozygous or homozygous for such deficiency. The present invention further provides the use of any of the above mice and cell lines in situations where the absence of at least one RAR or RXR receptor(s), or the normal expression thereof, is desirable.

Abstract: The invention provides a nonhuman transgenic animal having a transgene disrupting or interfering with expression of G.alpha..sub.q chromosomally integrated into the germ cells of the animal. Cells and cell lines derived from these nonhuman transgenic animals; a method for producing a transgenic nonhuman animal having a phenotype characterized by expression of a transgene which is otherwise not naturally occurring, where the expression of the transgene disrupts or interferes with G.alpha..sub.q activity; a method for determining an effect of an agent on G.alpha..sub.q expression, by administering an effective amount of the agent to a transgenic nonhuman animal having a transgene disrupting or interfering with G.alpha..sub.q, and measuring a physiological response of the transgenic nonhuman animal to the agent, and comparing the physiological response of the transgenic nonhuman animal having a transgene disrupting or interfering with G.alpha..sub.q to a control animal is also provided.

Abstract: The present invention relates to a transgenic non-human mammal comprising a DNA sequence encoding human extracellular superoxide dismutase (human EC-SOD) or a variant thereof which is expressed in the milk. Transgenic mice containing a chimeric whey acidic protein gene promoter operatively linked to human EC-SOD gene were produced. Levels of up to 0.7 mg human EC-SOD protein/mL milk were observed. The mammalian expression system is preferably expressed in a non-human mammal selected from the group containing rabbits, mice, rats, goats, sheep, pigs, llama, camels and bovine species. The human EC-SOD proteins dismutate superoxide radicals and bind heparin. Within the scope of the invention are also method for producing a transgenic non-human mammal capable of expressing human EC-SOD as defined above, and methods of making milk and methods of isolating protein from the milk.

Abstract: The present invention relates to utrons, RNA molecules which contain promoter regulatory motif(s) and DNA analogs thereof and DNA molecules that can be transcribed to produce the foregoing. In particular, the invention provides gene promoter suppressing nucleic acids which suppress transcription from a promoter of interest. In a preferred embodiment, the invention provides the TSU gene, nucleotide sequences of the TSU gene and RNA, as well as fragments, homologs and derivatives thereof. Methods of isolating TSU genes are also provided. Therapeutic and diagnostic methods and pharmaceutical compositions are also provided. In particular, the invention relates to methods for cell replacement therapy, gene therapy or organ transplantation wherein TSU nucleic acids suppress MHC class I and II gene expression, thus preventing immuno-rejection of non-autologous cells or organs.

Abstract: In accordance with the present invention, there are provided CRF overproducing transgenic mice which exhibit endocrine abnormalities involving the hypothalamic-pituitary-adrenal axis, such as elevated plasma levels of ACTH and glucocorticoids. The transgenic mice of the present invention represent a genetic model of CRF overproduction, providing a valuable tool for investigating the long term effects of CRF excess and dysregulation in the central nervous system.

Abstract: This present invention relates to the findings of the DNA sequences of fish insulin-like growth factor II (IGF-II) promoter regions and recombinant IGF-II promoters. These DNA sequences are capable of being expressed in eukaryotic cells and fish embryos of another fish species. The integration of the IGF-II promoter regions or recombinant IGF-II promoters into fish of another species results in the creation of a transgenic fish. The results of this invention illustrate that a fish IGF-II promoter not only can act as a growth factor to stimulate the growth and development of fish, but also is capable of being expressed in other eukaryotic cells such as in human cells.

Abstract: A process for producing a transgenic mouse which contains and expresses the human insulin hormone gene. The insulin gene is expressed only in the pancreas of the transgenic mouse and is regulated by glucose, glucagon, or other insulin affectors in a manner which is indistinguishable from that of normal mice. Progeny of the trangenic mice inherit the human insulin gene in a Mendelian manner, with approximately 50% of the mice of each litter expressing the human insulin gene. The weights of the transgenic mice, growth rate, feeding behavior, reproductive capability, and longevity appear indistinguishable from normal mice. The mice are useful for studies of pharmacokinetics of insulin expression and for investigations of possible drug interactions with glucose homeostasis.

Abstract: Provided are transgenic mice genetically engineered for a deficiency of the heart-skeletal muscle isoform of the adenine nucleotide translocator protein (Ant1). These mice exhibit histological, biochemical and physiological signs of deficiency in oxidative phosphorylation and energy generation, and these mice provide the first animal model for mitochondrial myopathy and hypertrophic cardiomyopathy. This animal model is used in methods for testing compounds for therapeutic value in treating failure to exchange ATP and ADP across the mitochondrial inner membrane, OXPHOS deficiency and in treating cardiac hypertrophy.

Abstract: A transgenic mouse whose genome comprises a disruption of the endogenous growth differentiation factor-11 (GDF-11) gene is disclosed. Also disclosed are methods for making such mice. The mice exhibit a phenotype of increased muscle tissue.

Abstract: A mouse which is homozygous for a disruption in the IDUA gene, but which has normal expression for the SAT-1 gene can be used for evaluating therapeutic agents for use in treating mucopolysaccharidosis Type I, by administering the therapeutic agent to the mouse, and evaluating the mouse for tissue pathology associated with iduronidase deficiency. The mouse can also be used for evaluating the ability of a targeting system to deliver a therapeutic agent to selected tissues or organs by administering an effective iduronidase replacement therapy coupled to the targeting system to a mouse which is homozygous for a disruption in the IDUA gene, but which has normal expression for the SAT-1 gene; and evaluating at least the selected tissue or organ from the mouse for pathology associated with iduronidase deficiency. Targeting systems which can be evaluated using this methodology include targeting moieties which selectively bind to or associate with selected cell types and in vivo and ex vivo gene therapy systems.

Abstract: A transgenic mouse with alterations in the H2-Ma gene is prepared by introduction of an altered H2-Ma gene into a host mouse. The resulting transgenic mice do not produce functional H2-M molecules.

Abstract: Disclosed is a method for the production of deletions in the chromosomal DNA of a single eukaryotic cell. More specifically, the method involves the creation of either random chromosomal deletions, or chromosomal deletions within a predetermined genetic loci. The deletions are created by integration of a DNA construct into the chromosomal DNA of the single eukaryotic cell, followed by spontaneous or irradiation induced deletion of the DNA construct from the chromosomal DNA. Also, disclosed is a method for the production of deletions in the chromosomal DNA of a multicell organism using a DNA construct.

Abstract: A transgenic mouse whose genome comprises a disruption of the endogenous growth differentiation factor-8 (GDF-8) gene is disclosed. Also disclosed are methods for making such mice. The transgenic mice exhibit a phenotype of increased muscle tissue.

Abstract: The present invention provides a transgenic mouse containing a transgene, said transgene comprising a truncated Nur77 (.DELTA.Nur77) gene. Also provided is a double transgenic mouse, wherein said double transgenic mouse comprises the .DELTA.Nur77 transgenic mouse backcrossed with the D.sup.b /HY T cell receptor transgenic mouse.

Abstract: The present invention provides a transgenic mouse comprising a disrupted hepsin gene. In particular, the invention provides methods of making the transgenic mouse comprising the disrupted hepsin gene by utilizing a hepsin targeting vector for homologous recombination in mouse embryonic stem cells. Also, nucleotide and amino acid hepsin sequences are disclosed.

Abstract: The subject invention provides non-human mammalian hosts characterized by inactivated endogenous Ig loci. The hosts are produced by repetitive transformations of embryonic stem cells by homologous recombination, preferably in conjunction with breeding. Different strategies are employed for recombination of the human loci randomly or at analogous host loci.

Abstract: Transgenic mice carrying two transgenes, the first coding for a transactivator fusion protein comprising a tet repressor and a polypeptide which directly or indirectly activates in eucaryotic cells, and the second comprising a gene operably linked to a minimal promoter operably linked to at least one tet operator sequence, are disclosed. Isolated DNA molecules (e.g., targeting vectors) for integrating a polynucleotide sequence encoding a transactivator of the invention at a predetermined location within a second target DNA molecule by homologous recombination are also disclosed. Transgenic mice having the DNA molecules of the invention integrated at a predetermined location in a chromosome by homologous recombination are also encompassed by the invention. Methods to regulate the expression of a tet operator linked-gene of interest by administering tetracycline or a tetracycline analogue to a mouse of the invention are also disclosed.

Abstract: The present invention relates to transgenic mice in which the biological function of at least one cell cycle regulatory proteins of the INK4 family is altered.

Abstract: Disclosed are transgenic mice that produces prostate tumors and faithfully recapitulate many of the features of human prostatic carcinoma. It has been discovered that transcriptional regulatory elements active in Paneth cells, granule goblet cells, intermediate cells, or a combination, when used to express Simian Virus 40 large T antigen (TAg) in a transgenic mouse leads to development of prostate tumors in the mouse. The transcriptional regulatory elements are derived from the cryptdin-2 (CR2) gene. The disclosed mice develop prostatic intraepithelial neoplasia (PIN) at an early age. Progression with local invasion, loss of androgen-dependence and eventual metastases are hallmarks of the disclosed transgenic mice.

Abstract: The invention features a method which includes the following steps: (a) introducing a transgene into a zygote of a dwarf goat, (b) transplanting the zygote into a pseudopregnant non-dwarf goat, and (c) allowing the zygote to develop to term. In another aspect the invention features a method which includes the following steps: (a) introducing a transgene into an embryo of a dwarf goat, (b) transplanting the embryo into a pseudopregnant non-dwarf goat, and (c) allowing the embryo to develop to term.

Abstract: Production of human procollagen or collagen in cells which ordinarily do not produce these molecules is effected by constructing expression systems compatible with mammary glands of non-human mammals. For example, expression systems can be microinjected into fertilized oocytes and reimplanted in foster mothers and carried to term in order to obtain transgenic non-human mammals capable of producing milk containing recombinant human procollagen or collagen. Human procollagen or collagen produced in this manner can be made of a single collagen type uncontaminated by other human or non-human collagens.