Massachusetts Institute of Technology

Leland Stanford Junior University

The Rockefeller University

Tufts University

Mass. Institute of Technology

Susumu Tonegawa

David M Kranz

Herman N Eisen

Haruo Saito

Maria Karayiorgou

Tsuyoshi Miyakawa

Randall S Johnson

Peter Mombaerts

Stephen D Gillies

David J Gerber

Virginia Papaioannou

Bridget Dolan

Mansuo Hayashi

The present invention provides targets, methods, and reagents for the diagnosis and treatment of schizophrenia and related conditions. The invention provides methods for the diagnosis of schizophrenia and susceptibility to schizophrenia by detection of polymorphisms, mutations, variations, alterations in expression, etc., in calcineurin genes or calcineurin interacting genes, or polymorphisms linked to such genes. The invention provides oligonucleotides, arrays, and antibodies for detection of polymorphisms and variants. The invention provides transgenic mice having alterations in such genes. The invention also provides methods of treating schizophrenia by administering compounds that target these genes. The invention further provides screening methods for identifying such compounds and compounds obtained by performing the screens.

Identifying calcineurin activators for treatment of schizophrenia

Disclosed is a heterodimeric T lymphocyte receptor subunit. The subunit consists of variable, joining, constant, transmembrane, and cytoplasmic regions. The structure, amino acid, and nucleotide sequence of the lymphocyte receptor subunit were determined using cDNA clones derived from a functional murine cytotoxic T lymphocyte clone. The genes corresponding to these cDNA are expressed and rearranged specifically in T cells and have significant sequence homologies to immunoglobulin V and C genes. T cell receptor subunits may be produced from the cDNA clones. The protein molecules may be further used for the production of T-cell clone specific antibodies.

Heterodimeric T lymphocyte receptor subunit

Disclosed is a heterodimeric T lymphocyte receptor subunit. The subunit consists of a signal peptide, variable, joining, constant, transmembrane, and cytoplasmic regions. The structure, amino acid, and nucleotide sequence of the lymphocyte receptor subunit were determined using cDNA clones derived from a functional murine cytotoxic T lymphocyte clone. The genes corresponding to these cDNA are expressed and rearranged specifically in T cells and have significant sequence homologies to immunoglobulin V and C genes. T cell receptor subunits may be produced from the cDNA clones. The protein molecules may be further used for the production of T-cell clone specific antibodies.

Heterodimeric T lymphocyte receptor

Immunodeficient animals are generated by introducing a mutation in RAG-1 into the germline of the animals via gene targeting in embryonic stem cells. The production of mutant RAG-1 deficient mice is detailed. RAG-1 deficient mice have no mature B and T lymphocytes. The arrest of B and T cell differentiation occurs at an early stage and correlates with the inability to perform V(D)J recombination. To date, these mice do not have mature B and T lymphocytes, nor do they express immunoglobulin or T cell receptors. The same strategy can be applied to the generation of other RAG-1 deficient animals, such as rabbits, rats, and pigs, using known techniques. These animals are all useful for the same general purposes as the scid mice, for example, cultivation of human lymphocytes for expression of human immunoglobulin. Other uses include the establishment of continuous lymphoid cell lines and, by crossbreeding with other lines of animals, the establishment of animals developing tumors for use in studying tumor cell developments and treatments.

Mutant RAG-1 deficient animals having no mature B and T lymphocytes

Disclosed is a heterodimeric T lymphocyte receptor subunit. The subunit consists of variable, joining, constant, transmembrane, and cytoplasmic regions. The structure, amino acid, and nucleotide sequence of the lymphocyte receptor submit were determined using cDNA clones derived from a functional murine cytotoxic T lymphocyte clone. The genes corresponding to these cDNA are expressed and rearranged specifically in T cells and have significant sequence homologies to immunoglobulin V and C genes. T cell receptor subunits may be produced from the cDNA clones. The protein molecules may be further used for the production of T-cell clone specific antibodies.

Disclosed is a heterodimeric T lymphocyte receptor comprising an alpha and a beta subunit. Each subunit consists of a signal peptide, variable, joining, constant, transmembrane, and cytoplasmic regions. The two subunits are connected by a disulfide bond between cysteine residues located between the constant and transmembrane region. The structure, amino acid, and nucleotide sequence of the lymphocyte receptor were determined using cDNA cones derived from a functional murine cytotoxic T lymphocyte clone. The genes corresponding to these cDNA are expressed

Meterodimeric T lymphocyte receptor antibody

Disclosed is a heterodimeric T lymphocyte receptor comprising an alpha and a beta subunit. Each subunit consists of a signal peptide, variable, joining, constant, transmembrane, and cytoplasmic regions. The two subunits are connected by a disulfide bond between cysteine residues located between the constant and transmembrane region. The structure, amino acid, and nucleotide sequence of the lymphocyte receptor were determined using CDNA clones derived from a functional murine cytotoxic T lymphocyte clone. The genes corresponding to these cDNA are expressed and rearranged specifically in T cells and have significant sequence homologies to immunoglobulin V and C genes. Both the T cell receptor protein and its subunits may be produced from the cDNA clones. The protein molecules may be further used for the production of T-cell clone specific antibodies.

Disclosed is a heterodimeric T lymphocytes receptor subunit. The subunit consists of variable, joining, constant, transmembrane, and cytoplasmic regions. The structure, amino acid, and nucleotide sequence of the lymphocyte receptor subunit were determined using cDNA clones derived from a functional murine cytotoxic T lymphocyte clone. The genes corresponding to these cDNA are expressed and rearranged specifically in T cells and have significant sequence homologies to immunoglobulin V and C genes. T cell receptor subunits may be produced from the cDNA clones. The protein molecules may be further used for the production of T-cell clone specific antibodies.

T lymphocyte receptor subunit

Disclosed is a heterodimeric T lymphocyte receptor comprising an alpha and a beta subunit. Each subunit consists of a signal peptide, variable, joining, constant, transmembrane, and cytoplasmic regions. The two subunits are connected by a disulfide bond between cysteine residues located between the constant and transmembrane region. The structure, amino acid, and nucleotide sequence of the lymphocyte receptor were determined using cDNA clones derived from a functional murine cytotoxic T lymphocyte clone. The genes corresponding to these cDNA are expressed and rearranged specifically in T cells and have significant sequence homologies to immunoglobulin V and C genes. Both the T cell receptor protein and its subunits may be produced from the cDNA clones. The protein molecules may be further used for the production of T-cell clone specific antibodies.

Disclosed is a method of enhancing expression of recombinant DNA in eucaryotic cells. A tissue specific enhancer element obtained from the genome of an organism and active in a selected tissue type is combined with a transcriptionally competent transcription unit comprising a promoter and exons encoding for the proteinaceous material of interest (or its precursor). This recombinant DNA is transfected into cells derived from the same tissue as the tissue in which the enhancer element normally functions to enhance expression of endogeneous DNA. The resulting transformants express the exons of the transcription unit at high levels as the enhancer element increases the copy number of mRNA. The enhancer element operates to increase transcription independent of its orientation and position provided it is located within an active region on the DNA, generally between about 1-10 kilobases (kb) from the 3' or 5' end of the transcription unit.

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Chestnut Hill, MA, United States of America

Susumu Tonegawa