Merck + Co., Inc.

Other

The Wellcome Trust Limited As Trustee for the Wellcome Trust

John W Hess

Michael S Phillips

Joseph A Borkowski

Patricia Hey

Michael L Metzker

David L Linemeyer

Charles T Caskey

Holly A Hammond

David L Gerhold

Yusuke Nakagawa

John G Menke

Yoshihiko Kawaguchi

John A Todd

Kathleen K Bierilo

Roger D Cox

Tony R Merriman

Catherine D Strader

C Thomas Caskey

Rebecca C J Twells

Doris F Cully

Leonardus H Van Der Ploeg

Qingyun Liu

Richard W Ransom

Howard Y Chen

Michael R Tota

Fang Chen

Myrna E Trumbauer

Rebecca Cj Twells

Sajjad A Qureshi

Charles I Rosenblum

A novel receptor, 'LDL-receptor-related protein-5' ('LRP-5'), is provided, along with encoding nucleic acid. The gene is associated with type 1 diabetes (insulin dependent diabetes mellitus), and experimental evidence provides indication that it is the IDDM susceptibility gene IDDM4. In various aspects the invention provides nucleic acid, including coding sequences, oligonucleotide primers and probes, polypeptides, pharmaceutical compositions, methods of diagnosis or prognosis, and other methods relating to and based on the gene, including methods of treatment of diseases in which the gene may be implicated, including autoimmune diseases, such as glomerulonephritis, diseases and disorders involving disruption of endocytosis and/or antigen presentation, diseases and disorders involving cytokine clearance and/or inflammation, viral infection, elevation of free fatty acids or hypercholesterolemia, osteoporosis, Alzheimer's disease, and diabetes.

Method of screening for modulator of LRP5 activity

A novel receptor, &ldquo;LDL-receptor related protein-3&rdquo; (&ldquo;LRP-3&rdquo;), is provided, along with encoding nucleic acid. The gene is associated with type 1 diabetes (insulin dependent diabetes mellitus), and experimental evidence provides indication that it is the IDDM susceptibility gene IDDM4. In various aspects the invention provides nucleic acid, including coding sequences, oligonucleotide primers and probes, polypeptides, pharmaceutical compositions, methods of diagnosis or prognosis, and other methods relating to and based on the gene, including methods of treatment of diseases in which the gene may be implicated, including autoimmune diseases, such as glomerulonephritis, diseases and disorders involving disruption of endocytosis and/or antigen presentation, diseases and disorders involving cytokine clearance and/or inflammation, viral infection, elevation of free fatty acids or hypercholesterolemia, osteoporosis, Alzheimer's disease, and diabetes.

LDL-receptor

Receptor

The present invention is a cloned human BK-2 bradykinin receptor cloned from a human lung fibroblast cell line. A cDNA clone, also part of the instant invention, encodes a novel 364 amino acid protein (the BK-2 receptor) that has the characteristics of a seven transmembrane domain G-protein coupled receptor. The invention is used to express a BK-2 bradykinin receptor in a host mammalian cell to screen for pharmaceutical antagonists or agonists which bind to or interact with the BK-2 bradykinin receptor protein.

Cloned and expressed human bradykinin BK-2 receptor

DNAs encoding bradykinin B,receptors from mammalian cells have been cloned and characterized. The recombinant receptor is capable of forming receptors which bind desArg,kallidin and other B,-specific ligands. The DNA has been expressed in recombinant host cells which produce active recombinant protein. In addition, the recombinant host cells are utilized to establish a method for identifying modulators of the receptor activity, and receptor modulators are identified.

Bradykinin B1 receptor antibodies

The rat ob receptor gene has been isolated and cloned. Two different alleles have been identified: the wild-type, and the fa-allele which differs from the wild type by only one base pair. The base pair change, however introduces an MspI restriction site into the DNA sequence, and also results in an amino acid change. Also part of the invention are the receptors, vectors containing the nucleic acid encoding the receptors, host cells transformed with this gene, and assays which use the gene or protein and identify new ligands.

Rat ob-receptors and nucleotides encoding them

The ob receptor has numerous isoforms resulting from alternative splicaing; three novel isoforms, designated c&prime;, f, and g are disclosed. The nucleic acids encoding these isoforms are taught. Also part of the invention are vectors containing the nucleic acid encoding the receptors, host cells transformed with these genes, and assays which use the genes or protein isoforms.

OB receptor isoforms and nucleic acids encoding them

A trans-activation assay for leptin is described. Leptin response elements are located proximal to a promoter, and the promoter region is operatively linked to a reporter gene. When leptin binds with the receptor, the reporter gene is transcribed.

Leptin assay

DNAs encoding bradykinin B.sub.1 receptors from mammalian cells have been cloned and characterized. The recombinant receptor is capable of forming receptors which bind des-Arg.sup.10 kallidin and other B.sub.1 -specific ligands. The DNA has been expressed in recombinant host cells which produce active recombinant protein. In addition, the recombinant host cells are utilized to establish a method for identifying modulators of the receptor activity, and receptor modulators are identified.

Purified bradykinin B.sub.1 receptor

A transgenic non-human animal with alterations in a bradykinin B2 receptor gene is prepared by introduction of a gene encoding an altered bradykinin B2 receptor into a host non-human animal.

Bradykinin B2 receptor modified transgenic non-human animals

DNA encoding bradykinin B1 receptor

A cryogenically efficient interface which enables the quick loading of completely configured Independent Measurement Inserts in a direction perpendicular to the temperature gradient of a cryogenic cooling source. An air lock and precooling means provide a method for loading independent measurement inserts directly into the cryostat vacuum without applying an undue initial or steady thermal load on the cooling source. A heat switch provides means for establishing variable thermal contact between the contoured independent measurement inserts and the cold stage of a cryogenic cooling source. There is a free selection in the cryogenic cooling source which may be used and also in the types of measurements which may be configured and loaded by the means of appropriately configured idependent measurement inserts. Loading of measurement inserts may be carried out in any direction. The experimental flexibility gained in the use of my invention is a benefit to scientists and engineers wishing to conveniently perform a diversity of different measurements at cryogenic temperatures.

Cryogenic interface for perpendicular loading of independent measurement

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Lansdale, PA, United States of America

John W Hess