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1. WO2007139926 - CRAC CHANNEL AND MODULATOR SCREENING METHODS

Publication Number WO/2007/139926
Publication Date 06.12.2007
International Application No. PCT/US2007/012469
International Filing Date 24.05.2007
IPC
C12N 15/85 2006.01
CCHEMISTRY; METALLURGY
12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
15Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
09Recombinant DNA-technology
63Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
79Vectors or expression systems specially adapted for eukaryotic hosts
85for animal cells
C12N 5/06 2006.01
CCHEMISTRY; METALLURGY
12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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5Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
06Animal cells or tissues
C12N 15/00 2006.01
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C12N 15/63 2006.01
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12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
15Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
09Recombinant DNA-technology
63Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
C07H 21/04 2006.01
CCHEMISTRY; METALLURGY
07ORGANIC CHEMISTRY
HSUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
21Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
04with deoxyribosyl as saccharide radical
CPC
A61P 35/00
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
35Antineoplastic agents
C07K 14/705
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07ORGANIC CHEMISTRY
KPEPTIDES
14Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
435from animals; from humans
705Receptors; Cell surface antigens; Cell surface determinants
G01N 2500/02
GPHYSICS
01MEASURING; TESTING
NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
2500Screening for compounds of potential therapeutic value
02Screening involving studying the effect of compounds C on the interaction between interacting molecules A and B (e.g. A = enzyme and B = substrate for A, or A = receptor and B = ligand for the receptor)
G01N 33/6872
GPHYSICS
01MEASURING; TESTING
NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
33Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
48Biological material, e.g. blood, urine
50Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
68involving proteins, peptides or amino acids
6872Intracellular protein regulatory factors and their receptors, e.g. including ion channels
G16B 10/00
GPHYSICS
16INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
BBIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
10ICT specially adapted for evolutionary bioinformatics, e.g. phylogenetic tree construction or analysis
G16B 30/00
GPHYSICS
16INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
BBIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
30ICT specially adapted for sequence analysis involving nucleotides or amino acids
Applicants
  • THE REGENTS OF THE UNIVERSITY OF CALIFORNIA [US]/[US] (AllExceptUS)
  • CAHALAN, Michael, D. [US]/[US] (UsOnly)
  • ZHANG, Shenyuan, L. [CN]/[US] (UsOnly)
  • YEROMIN, Andriy, V. [UA]/[US] (UsOnly)
Inventors
  • CAHALAN, Michael, D.
  • ZHANG, Shenyuan, L.
  • YEROMIN, Andriy, V.
Agents
  • LANDRY, Stacy, M.
Priority Data
60/808,73326.05.2006US
60/830,94814.07.2006US
60/834,23428.07.2006US
Publication Language English (EN)
Filing Language English (EN)
Designated States
Title
(EN) CRAC CHANNEL AND MODULATOR SCREENING METHODS
(FR) CANAL CRAC ET PROCÉDÉS DE CRIBLAGE PAR MODULATEUR
Abstract
(EN)
Recent studies by our group and others demonstrated a required and conserved role of Stim in store-operated Ca2+ (SOC) influx and Ca2+ release-activated Ca2+ (CRAC) channel activity. Using an unbiased genome-wide RNAi screen in Drosophila S2 cells, 75 hits were identified that strongly inhibited Ca2+ influx upon store emptying by thapsigargin (TG). Among these hits are 11 predicted trans membrane proteins, including Stim and one, olf186-F, that upon RNAi-mediated knockdown exhibited a profound reduction of TG-evoked Ca2+ entry and CRAC current, and upon over expression a three- fold augmentation of CRAC current. CRAC currents were further increased to eight-fold higher than control and developed more rapidly when olf186-F was co-transfected with Stim. olf186-F is a member of a highly conserved family of four-trans membrane spanning proteins with homo logs from C. elegans to human. The ER Ca2+ pump SERCA and the SNARE protein Syntaxin5 were also required for CRAC channel activity, consistent with a signaling pathway in which Stim senses Ca2+ depletion within the ER, trans locates to the plasma membrane, and interacts with olf186-F to trigger CRAC channel activity.
(FR)
Des études récentes réalisées par notre groupe et d'autres ont montré un rôle nécessaire et conservé de Stim dans l'influx de Ca2+ activé par réserve (SOC) et l'activité du canal calcique activé par libération de Ca2+ (CRAC). En utilisant un crible d'ARN interférent non polarisé s'étendant sur tout le génome dans des cellules de Drosophila S2, on a identifié 75 réponses qui inhibaient de manière importante un influx de Ca2+ au moment du vidage de la réserve par thapsigargine (TG). Parmi ces réponses, on prévoit que 11 soient des protéines transmembranaires, dont Stim et une, olf186-F, qui au moment de l'inactivation déclenchée par ARN interférent, a montré une profonde réduction de l'entrée de Ca2+ évoquée par TG et du courant du CRAC, et au moment d'une sur-expression, une augmentation trois fois supérieure du courant du CRAC. Des courants de CRAC ont été en outre augmentés jusqu'à huit fois un témoin et ils se sont développés plus rapidement quand olf186-F était co-transfecté par Stim. olf186-F appartient à une famille très conservée de quatre protéines transmembranaires avec des homologues de C. elegans chez l'homme. La pompe à Ca2+ ER SERCA et une protéine SNARE, la Syntaxine 5, ont aussi été nécessaires pour l'activité du canal CRAC, correspondant à une voie de signalisation dans laquelle Stim détecte une déplétion de Ca2+ au sein de ER, se déplace vers la membrane plasmatique, et interagit avec olf186-F pour déclencher une activité du canal CRAC.
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