WO1995018140A1 - Genes et recepteurs olfactifs - Google Patents

Genes et recepteurs olfactifs Download PDF

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Publication number
WO1995018140A1
WO1995018140A1 PCT/US1994/014554 US9414554W WO9518140A1 WO 1995018140 A1 WO1995018140 A1 WO 1995018140A1 US 9414554 W US9414554 W US 9414554W WO 9518140 A1 WO9518140 A1 WO 9518140A1
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Prior art keywords
protein
polypeptide
dna sequence
dna
sequence
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PCT/US1994/014554
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English (en)
Inventor
Nissim Ben-Arie
Doron Lancet
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Yeda Research & Development Co., Ltd.
Rycus, Avigail
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Application filed by Yeda Research & Development Co., Ltd., Rycus, Avigail filed Critical Yeda Research & Development Co., Ltd.
Publication of WO1995018140A1 publication Critical patent/WO1995018140A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants

Definitions

  • the present invention is generally in the field of human genetics and concerns genes of the human olfactory system.
  • the genetic basis for the olfactory system has been subject to extensive research. An understanding of the genetic basis of olfaction is important, for example, for the fragrance industry, to enable a more systematic and accurate way of fragrance design. To date, research in this field has been centered primarily in non-human mammals, although some information on the genetic basis of the olfactory system in humans has also been found.
  • ORs olfactory receptors
  • OR gene clusters human OR genes form continuous clusters in the genome.
  • OR gene clusters One such OR gene cluster was found on human chromosome 17. This OR gene cluster was found to be about 0.35 Mb long with an average inter-genic separation between the genes of about 15 kb.
  • the present invention thus provides, by a first of its aspects, a DNA molecule selected from the group consisting of: (a) an isolated cluster of olfactory receptor genes;
  • a specific olfactory receptor gene cluster in accordance with the invention is that located on human chromosome 17 or that located on human chromosome 11.
  • a DNA molecule having a coding sequence being a member selected from the group consisting of: (a) a DNA sequence depicted in Fig. 4 with the proviso that the sequences designated 17-2 and 17-4 be excluded;
  • the above DNA molecules can be used in transforming a host cell to express the protein or polypeptide encoded by said DNA molecule.
  • the DNA molecule is incorporated into an expression vector which is introduced into suitable host cells, which may be prokaryotic or eukaryotic.
  • Eukaryotic host cells are generally preferred since the post- translational modification in prokaryotic and eukaryotic host cells is different, and thus expression in a eukaryotic host cell will bring to an expression product which more closely resembles that encoded by the olfactory genomic DNA in humans.
  • a particular example of a vector and a host cell is the Baculovirus vector and an insect host cell, respectively.
  • the present invention thus provides a method of production of a protein or a polypeptide in a host cell comprising transforming a host cell by a DNA molecule selected from those defined above, growing the host cells under conditions allowing for expression of the protein or polypeptide encoded by said DNA molecule and harvesting the expressed product.
  • a protein or polypeptide encoded by the above coding sequence and being a member selected from the group consisting of: (a) a protein or polypeptide having an amino acid sequence depicted in Fig. 3;
  • the present invention also provides, by a further of its aspects, uses of the above DNA molecules, proteins or polypeptides.
  • Another use of the DNA molecule is in the construction of probes for use in studying olfactory polymorphism in a population or of probes for Southern blot hybridization and restriction fragment length polymorphism for detecting interindividual differences in olfactory receptors or olfactory clusters in humans.
  • Useful for this purpose are characterizing fragments of an OR gene cluster or DNA sequence which hybridize thereto.
  • the integrity of gene clusters is usually preserved over generations, i.e. gene clusters are usually inherited as a single unit. This is so since the recombination between pairs of chromosomes has a much higher probability of occurring outside such clusters.
  • a fragrance preparation can be produced which will create a positive response in most individuals.
  • the proteins or polypeptides of the invention may be used in probing for the presence of a certain fragrance, aroma or flavor in a medium. Another use of said polypeptides or proteins is in the development of fragrances for human use.
  • said protein or polypeptide When used in probing or in the development of fragrances, said protein or polypeptide may be immobilized onto a solid support or may be embedded into a suitable membraneous system, e.g. membrane of a host cell transformed with a DNA encoding for said protein or polypeptide displaying same on its surface, a liposome wherein said protein or polypeptide is embedded, and the like.
  • a further use of the above protein and polypeptide is in raising antibodies.
  • Such antibodies which also form an aspect of the invention, may be used to detect and label ORs in vivo as well as in in vitro prepara ⁇ tions.
  • the antibodies may carry a detectable marker.
  • Another use of the antibodies is in assays for the detection of the presence of fragrances in a medium.
  • antibodies which recognize the fragrance binding site are brought into contact with said proteins or polypeptides in the presence of a tested medium, the level of bound or free antibodies being directly proportional to the level of fragrance in the tested medium.
  • the DNA molecules and proteins or polypeptides of the invention may have various other uses, all being within the scope of the present invention.
  • Fig. 1 shows fluorescence in situ hybridization (FISH) of cosmid 7 to metaphase spreads of human chromosomes.
  • FISH fluorescence in situ hybridization
  • Fig. 2 shows the mapping of the OR cluster in human 17pl3.3.
  • Thirty-six representative OR-positive cosmids from the human chromosome 17 library were assembled into 3 contigs utilizing a partial digest mapping technique.
  • the Hindl ⁇ l (H) and EcoRl (E) sites are shown on the top lines.
  • the numbered cosmids are shown as horizontal line, showing their positions in the contig.
  • Gap lengths between the 3 contigs were estimated to be 10-20 kb by FISH to free chromatin, and are shown to scale.
  • OR coding regions mapped to within ⁇ 4kb are shown as dark boxes, while those for which only a cosmid assignment is known are shown as open boxes.
  • Fig. 3 shows the deduced amino acid sequences of olfactory receptor clones from human chromosome 17 and their alignment.
  • the deduced protein sequences of the PCR-generated clones encoding putative human ORs were aligned using the GCG package pileup program (Genetic Computer Group, Madison, Wisconsin, U.S.A.).
  • Rat OR I14 1 is also included for comparison and positioning of the sequences in the full length open reading frame. The numbering system used is based on the 114 sequence. Transmembrane domains were determined by an averaged hydropathy plot procedure combined with a hydrophobic moment analysis and are marked by lines with roman numerals. Dark boxes represent amino acids identity, while different shades of gray stand for two different degrees of conservative substitutions.
  • ORs 17-23 and 17-90 have a deletion of one nucleotide compared to all other sequences, which leads to an immediate stop codon to be in frame. Therefore, amino acid 166 in these sequences was marked as *, and the remainder of the protein is the translation of the phase deduced by homology to the other OR sequences;
  • Fig. 4 shows the DNA sequences of the olfactory receptors from the human chromosome 17 cluster shown in Fig. 3;
  • Fig. 5 shows the expression of OR17-93 in human olfactory epitheli ⁇ um.
  • PCR analysis was performed using OR17-93 specific primers on the following templates; OR17-93 and OR17-2 clones as positive controls (OR), cDNA of olfactory epithelium (OR), cDNA of respiratory epithelium (RE), cDNA from nasal inverted papilloma (PA).
  • OR OR
  • RE cDNA of respiratory epithelium
  • PA nasal inverted papilloma
  • Arrows are pointing at the PCR products of OR17-93 and OR17-2 clones (260 and 230 bp, respectively).
  • M 100 bp ladder markers (BRL, Gaithersburg, MD).
  • Genomic DNA was extracted from male Wistar rats and from blood of a human individual.
  • the rat probe (ORI) was obtained by PCR using oligonucleotides OR5B (TM2; CCC ATG TA(T/C) TT(G/CVT) TT(C/T) CTC (A/G/T)(G/C) (C/T) AA(OT)(T/C)T(G/A) TC C) and OR3B (TM7; OR3B AG(A/G) C(A/T)(A/G) TAI ATG AAI GG(A/G) TTC AIC AT).
  • the human probe, ORIII was amplified by nested PCR, using first OR5B/OR3B and then reamplified by OR5A (GGC (QT)TA TGA CCG IT(A/T) (T/C)(G/C)T (G/A)GC (OT)AT ITG) and OR3B.
  • PCR amplifica ⁇ tion was carried out in a buffer containing 50mM KC1, lOmM Tris pH 8.3, 0.01% gelatine, 0.2 mM each deoxyribonucleotide, l M each primer and 2.5 U of Taq DNA polymerase (Cetus, Branchburg, NJ) lOO ⁇ l as follows: 30 cycles of denaturation at 94°C, annealing at 55°C and extension at 72°C, each step for 1 min. The first step of denaturation and the last step of extension were 4 min. long. Both PCR-generated probes were purified by Geneclean II (BIO 101, La Jolla, CA).
  • Chromosome 17 cosmid library was used, prepared previously from flow-sorted chromosome 17 DNA, isolated from human cell line LCL127 12 .
  • DNA probes were radiolabelled to a specificity activity of 10 s -10 9 cpm/ ⁇ g by random hexamer priming using [ -32P] dCTP (Amersham, Buckinghamshire, UK).
  • Hybridization to filters was carried out overnight in 50% formamide, 50 mM sodium phosphate buffer, pH 7.2, 1 mM EDTA, 10X Denhardt's, 4X SSC, 1% SDS, 10% dextran sulphate, 50 ⁇ g/ml sonicated salmon sperm DNA, and 100 ⁇ g/ml sonicated human placental DNA at 42°C.
  • Cosmid and genomic filters were washed in IX SSC, 0.1% SDS at room temperature for 60 minutes and exposed to Kodak XAR 5 X-ray film at -80°C. The positive cosmids isolated were numbered sequentially from 1 to 76. The isolation of 70 OR-positive cosmids (average insert length 35 kb) in a region of 350 kb suggests a 7- fold coverage of the library, over this region, in agreement with the previously estimated coverage.
  • Cosmid DNA was purified using a Qiagen column (Diagen, Chatsworth, CA) according to the manufacturer's recommendations.
  • a Qiagen column Diagen, Chatsworth, CA
  • cosmid DNA was linearised by cleavage with lambda terminase (lU/mg DNA) for 2 hours at room temperature and 2 ⁇ g partially digested with EcoRl or Hind ⁇ Jl in a total volume of 30 ⁇ l at 37°C (0.2 U/ g DNA, removing 5 ⁇ l aliquots every 5 minutes).
  • Partially digested cosmid DNA were hybridized in solution with radiolabelled oligonucleotides complemen ⁇ tary to the protruding 12bp single-stranded sequences at the cleaved cos site and the samples fractionated on a 0.5% agarose gel.
  • PCR amplification using OR5B and OR3B as primers was performed on individual cosmids.
  • the PCR products were digested with a frequent cutter restriction enzymes (e.g. Hinfl, Hael ⁇ l, Hhal).
  • a frequent cutter restriction enzymes e.g. Hinfl, Hael ⁇ l, Hhal.
  • the lengths of the fragments were summed and divided by the length of the undigested product, as described 1>2 -
  • the value obtained is the Minimal Complexity Index (MCI), indicating the minimal number of putative receptors encoded by the cosmid.
  • MCI Minimal Complexity Index
  • Cosmid DNA was extracted by the miniprep alkaline lysis procedure. PCR was performed separately on each, using OR5B/OR3B primers. An equimolar pool of PCR products from all cosmids, as well as products amplified from individual cosmids were ligated to pCRlOOO or pCRII plasmids (Invitrogene, San Diego, CA). Recombinant clones were identified by Southern blot hybridization and PCR.
  • Sequencing was performed using Taq DNA polymerase and dye-terminators on an ABI DNA sequencer model 373 A, with universal vector primers and HOR1, an internal primer (GA/(C/T) G(A/G)(A/C) T(A/T)(CVT) (G/QTG GCC ATG TGC).
  • FISH Fluorescence in situ hybridization
  • Hybridization and detection were carried out according to a modification of the technique described by Pinkel et al. u .
  • 1 ⁇ g of cosmid DNA was biotinylated using a Bionick kit (BRL, Gaithersburg, MD).
  • 80 ng of labelled DNA was mixed with 4 ⁇ g Cot-1 DNA (BRL, Gaithersburg, MD), dried and resuspended in hybridiza ⁇ tion buffer (50% formamide, 2xSSC, 10% dextran sulphate, 1% Tween 20).
  • the sample was denatured by heating to 80°C for 3.5 minutes and incubated at 37°C for 60 minutes.
  • Chromosome slides were baked for two hours at 65°C and then denatured in 70% formamide, 2xSSC for 3 minutes at 75°C. Slides were dehydrated by washing with 70%, 95% and absolute ethanol. Hybridization took place overnight at 37°C under sealed coverslip. Post hybridization washes were with 2xSSC. 50% formamide (3 x 5 min.) and 2xSSC (3 x 5 min.) both at 42°C.
  • the slides were then washed in 4xSSC, 0.05% Tween 20, pH 7 (SSCT) for 3 minutes at 37°C and preincubated in SSCT containing 5% low fat dried milk (Marvel) (SSCTM) prior to the addition of FITC-conjugated avidin DCS (Vector labs) at 5 g/ml in SSCT.
  • SSCTM low fat dried milk
  • the signal was amplified by addition of biotinylated anti-avidin (5 ⁇ g/ml) and a second application of FITC-avidin (DCS (5 ⁇ g/ml).
  • DCS FITC-avidin
  • Chromatin was released from routinely fixed nuclei according to a recently developed method 15 .
  • two color FISH one probe was labelled with biotin and one with digoxygenin, as above. Detection was by incubation with mouse anti-digoxygenin monoclonal antibody (Boehringer Manheim, Manheim, Germany) at 0.8 ⁇ g/ml plus avidin Texas red at 2 ⁇ g/ml, both in SSCTM. This was followed by anti-mouse IgG conjugated to FITC at 30 ⁇ g/ml. The biotinated anti-avidin was used alone and finally another round of avidin Texas red was performed. Post hybridization washes were as described.
  • Somatic cell hybrids BR8 and AY1 were constructed by fusion of lymphoblastoid cell lines of Miller-Dieker syndrome patients MDS-9 and MDS-12, respectively, with TK' rodent cells followed by selection in HAT media. Hybrid clones containing a single, detected chromosome 17 were identified by RLFP analysis of polymorphic loci in distal 17p and confirmed by cytogenetic analysis.
  • RNA expression Human tissues were surgically removed from a female patient having inverted papilloma and were immediately frozen in liquid nitrogen. Total RNA was extracted using TRI-REAGENT (NRC Inc., Cincinnati, OH) following the manufacturer's procedure. Yields were 3.3, 0.9 and 1.6 mg RNA/g tissue for papilloma, olfactory epithelium and respiratory epithelium, respectively. Total RNA (2 ⁇ g) was treated with 0.2 units reverse transcriptase (BRL, Gaithersburg, MD) for 20 mins.
  • OR17-93A ATT GCT GCA GAA CAT GCA GAA
  • OR17-93B ACA TGG CAT GGA AGG TGG TC.
  • a control experiment was conducted to verify that the PCR signals are RNA-dependent, and not due to a genomic DNA contamination. Since Taq DNA polymerase is known to have a significant reverse transcriptase activity, the omission of reverse transcription was considered less desirable. Instead, control PCR reactions were performed using primers for 3-actin spanning intron 2.
  • oligonucleotide primers OR5B and OR3B, respectively. These were utilized to amplify a complex set of OR-related sequences by polymerase chain reaction (PCR), using rat and human genomic DNA as templates (probes ORI and ORIII, respectively). The resulting PCR products were radiolabelled and used to screen cosmid libraries prepared from flow-sorted human chromosomes 17, 21, 22 and X 12 .
  • Chromosomal mapping of the OR gene cluster The approximate size of the genomic OR locus was determined by hybridizing the 5B/3A PCR products from cosmids, 1,2,4 and 7 to a Southern blot containing human genomic DNA digested with a variety of infrequently cutting restriction enzymes (BssHII, SacII, Mlul, Nrul and Not ⁇ ). All four PCR products identified a ⁇ 400 kb .BssHII restriction fragment, giving an estimate for the maximal size of the region. This indicated that the clustered OR genes do not have CpG islands at their 5' flanking ends.
  • Hind ⁇ il and EcoRl restriction maps were constructed for 40 cosmids using a partial digest mapping protocol 17 , and 35 of them arranged into three contigs with a total length of 347 kb (Fig. 2). All the other cosmids were judged by full restriction digest patterns with Hindlll to be overlapping with the mapped subset. Two small gaps were seen, which probably arise due to the large distance between neighboring OR genes in these regions. The gap sizes between cosmids 53-45, 53-68 and 28-65 were estimated at 10-20 kb, and the contigs oriented relative to each other, by two-color FISH 15 to free chromatin using pairwise combination of cosmids from the ends of the three established contigs (data not shown). This produced clear linear signals from cosmids hybridized to chromatin fibers, enabling the relationship between adjacent or overlapping probes to be determined. A more accurate localization and an absolute orientation of the
  • OR cluster within the chromosomal band 17pl3.3 was obtained using DNA from somatic cell hybrids containing the deleted human chromosome 17 homolog of two Miller-Dieker Syndrome (MDS) patients 16 .
  • DNA from hybrid BR8 was positive with the ORI 7-93 PCR primers but negative with PCR marker HP5 (near OR17-210) as well as with STS marker 506 16 which is found only on cosmid 73 (Fig. 2). Southern hybridization with cosmids 7, 44 and 59 further confirmed the location of the BR8 breakpoint at the centromeric end of the OR cluster, within cosmid 7.
  • DNA from hybrid AYl was positive with all three PCR markers, consistent with its breakpoint being telomeric to STS marker 506.
  • the OR cluster is localized between the BR8 breakpoint and STS 506, immediately centromeric to the MDS critical region.
  • OR17-2 and OR17-31 For the first pair (OR17-2 and OR17-31), the difference was one silent mutation (at amino acid 218).
  • the second pair For the second pair (ORI 7-23 and OR17-90, both pseudogenes with the same single base deletion at amino acid 166) the difference was a trinucleotide deletion in OR17-90, which affected two coded amino acids (positions 243-4).
  • These two OR gene pairs may be alleles, occurring at respectively identical loci on cosmids derived from the parental and maternal chromosomes. Alternative ⁇ ly, they could be the result of a recent tandem duplication.
  • OR genes described here were isolated from cloned genomic DNA fragments. To examine whether any of them are actually expressed in human olfactory epithelium, samples of olfactory and non-sensory nasal tissues from a human subject were obtained. Total RNA was extracted, and examined for OR expression by a reverse transcriptase - polymerase chain reaction (RT-PCR) assay (Fig. 5). A control PCR with -actin primers spanning an intron was used to demonstrate that signals are not significantly generated from a genomic DNA contamination. Since OR genes are rather similar to each other, it was necessary to verify that a specific OR of the presently described cluster is the one actually amplified. The verification made use of the unusual 27 nucleotide insertion in OR17-93 and this, together with the design of a specific primer pair allowed to ascertain that only one gene product was amplified.

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Abstract

Des gènes olfactifs se présentent sous forme de groupes de gènes. Dans le génome humain, ces groupes apparaissent sur les chromosomes 11 et 17. Ces groupes de gènes sont décrits ici pour la première fois. On a découvert et on décrit ici une variété de séquences d'ADN codant des récepteurs olfactifs ou des parties de ceux-ci.
PCT/US1994/014554 1993-12-28 1994-12-28 Genes et recepteurs olfactifs WO1995018140A1 (fr)

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IL108205 1993-12-28
IL10820593A IL108205A0 (en) 1993-12-28 1993-12-28 Olfactory genes and receptors

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Cited By (17)

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Publication number Priority date Publication date Assignee Title
WO2000021985A2 (fr) * 1998-10-14 2000-04-20 Genset Genes codant pour des recepteurs olfactifs et leurs marqueurs bialleliques
WO2001027158A2 (fr) * 1999-10-08 2001-04-19 Digiscents Sequences de recepteurs olfactifs
WO2001077155A2 (fr) * 2000-04-06 2001-10-18 Curagen Corporation Nouveaux polynucleotides et polypeptides codes par ces polynucleotides
WO2001081578A2 (fr) * 2000-04-26 2001-11-01 Curagen Corporation Nouvelles proteines et acides nucleiques codant ces dernieres
WO2002010202A2 (fr) * 2000-07-26 2002-02-07 Curagen Corporation Nouvelles proteines et nouveaux acides nucleiques codant celles-ci
WO2002012343A2 (fr) * 2000-08-07 2002-02-14 Curagen Corporation Nouvelles proteines et acides nucleiques les codant
WO2002012561A2 (fr) * 2000-08-03 2002-02-14 Genaissance Pharmaceuticals, Inc. Haplotypes du gene or1g1
WO2002050117A2 (fr) * 2000-12-18 2002-06-27 Curagen Corporation Proteines et acides nucleiques codant ces proteines
EP1944319A1 (fr) 2000-03-07 2008-07-16 Senomyx Inc. Récepteurs du goût T1R et gènes codant pour ceux-ci
EP1985630A2 (fr) 2001-01-03 2008-10-29 Senomyx, Inc. Récepteurs du gout T1R et gènes les codant
EP2149606A1 (fr) 2008-08-01 2010-02-03 International Flavors & Fragrances Inc. Molécules d'acide nucléique et procédés pour identifier les modulateurs de l'activité GPR84
WO2010123930A2 (fr) 2009-04-20 2010-10-28 Elcelyx Therapeutics, Inc. Thérapies à base de ligand de récepteur chimiosensible
WO2013158928A2 (fr) 2012-04-18 2013-10-24 Elcelyx Therapeutics, Inc. Thérapies à base de ligand de récepteur chimiosensoriels
US8828953B2 (en) 2009-04-20 2014-09-09 NaZura BioHealth, Inc. Chemosensory receptor ligand-based therapies
US9486463B2 (en) 2010-10-19 2016-11-08 Ambra Bioscience Llc Chemosensory receptor ligand-based therapies
US9901551B2 (en) 2009-04-20 2018-02-27 Ambra Bioscience Llc Chemosensory receptor ligand-based therapies
EP3763419A1 (fr) 2011-01-07 2021-01-13 Anji Pharma (US) LLC Traitements à base de ligand de récepteur chimiosensoriel

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CELL, Volume 65, issued 05 April 1991, L. BUCK et al., "A Novel Multigene Family May Encode Odorant Receptors: A Molecular Basis for Odor Recognition", pages 175-187. *
CYTOGENET. CELL GENET., Volume 63, issued 1993, S. SCHURMANS et al., "The OLFR1 Gene Encoding the HGMPO7E Putative Olfactory Receptor Maps to the 17p13-->p12 Region of the Human Genome and Reveals and MspI Restriction Fragment Length Polymorphism", pages 200-204. *
NATURE, Volume 355, issued 30 January 1992, M. PARMENTIER et al., "Expression of Members of the Putative Olfactory Receptor Gene Family in Mammalian Germ Cells", pages 453-455. *
NATURE, Volume 361, issued 28 January 1993, K. RAMING et al., "Cloning and Expression of Odorant Receptors", pages 353-356. *
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Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000021985A2 (fr) * 1998-10-14 2000-04-20 Genset Genes codant pour des recepteurs olfactifs et leurs marqueurs bialleliques
WO2000021985A3 (fr) * 1998-10-14 2000-08-03 Genset Sa Genes codant pour des recepteurs olfactifs et leurs marqueurs bialleliques
WO2001027158A3 (fr) * 1999-10-08 2002-09-26 Digiscents Sequences de recepteurs olfactifs
WO2001027158A2 (fr) * 1999-10-08 2001-04-19 Digiscents Sequences de recepteurs olfactifs
EP2298802A1 (fr) 2000-03-07 2011-03-23 Senomyx, Inc. Recepteurs gustatifs T1R3 et genes codant pour ces recepteurs
EP2143732A1 (fr) 2000-03-07 2010-01-13 Senomyx, Inc. Récepteurs du goût T1R1 et gènes codant pour ceux-ci
EP1944319A1 (fr) 2000-03-07 2008-07-16 Senomyx Inc. Récepteurs du goût T1R et gènes codant pour ceux-ci
WO2001077155A2 (fr) * 2000-04-06 2001-10-18 Curagen Corporation Nouveaux polynucleotides et polypeptides codes par ces polynucleotides
WO2001077155A3 (fr) * 2000-04-06 2003-09-25 Curagen Corp Nouveaux polynucleotides et polypeptides codes par ces polynucleotides
WO2001081578A2 (fr) * 2000-04-26 2001-11-01 Curagen Corporation Nouvelles proteines et acides nucleiques codant ces dernieres
WO2001081578A3 (fr) * 2000-04-26 2003-03-13 Curagen Corp Nouvelles proteines et acides nucleiques codant ces dernieres
WO2002010202A2 (fr) * 2000-07-26 2002-02-07 Curagen Corporation Nouvelles proteines et nouveaux acides nucleiques codant celles-ci
WO2002010202A3 (fr) * 2000-07-26 2003-04-10 Curagen Corp Nouvelles proteines et nouveaux acides nucleiques codant celles-ci
WO2002012561A2 (fr) * 2000-08-03 2002-02-14 Genaissance Pharmaceuticals, Inc. Haplotypes du gene or1g1
WO2002012561A3 (fr) * 2000-08-03 2003-09-25 Genaissance Pharmaceuticals Haplotypes du gene or1g1
WO2002012343A2 (fr) * 2000-08-07 2002-02-14 Curagen Corporation Nouvelles proteines et acides nucleiques les codant
WO2002012343A3 (fr) * 2000-08-07 2003-06-19 Curagen Corp Nouvelles proteines et acides nucleiques les codant
WO2002050117A3 (fr) * 2000-12-18 2003-08-14 Curagen Corp Proteines et acides nucleiques codant ces proteines
WO2002050117A2 (fr) * 2000-12-18 2002-06-27 Curagen Corporation Proteines et acides nucleiques codant ces proteines
EP1985630A2 (fr) 2001-01-03 2008-10-29 Senomyx, Inc. Récepteurs du gout T1R et gènes les codant
EP2149606A1 (fr) 2008-08-01 2010-02-03 International Flavors & Fragrances Inc. Molécules d'acide nucléique et procédés pour identifier les modulateurs de l'activité GPR84
WO2010123930A2 (fr) 2009-04-20 2010-10-28 Elcelyx Therapeutics, Inc. Thérapies à base de ligand de récepteur chimiosensible
US8828953B2 (en) 2009-04-20 2014-09-09 NaZura BioHealth, Inc. Chemosensory receptor ligand-based therapies
US9901551B2 (en) 2009-04-20 2018-02-27 Ambra Bioscience Llc Chemosensory receptor ligand-based therapies
US9486463B2 (en) 2010-10-19 2016-11-08 Ambra Bioscience Llc Chemosensory receptor ligand-based therapies
EP3763419A1 (fr) 2011-01-07 2021-01-13 Anji Pharma (US) LLC Traitements à base de ligand de récepteur chimiosensoriel
WO2013158928A2 (fr) 2012-04-18 2013-10-24 Elcelyx Therapeutics, Inc. Thérapies à base de ligand de récepteur chimiosensoriels

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