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BioAssay: AID 2325

Summary of probe development efforts to identify agonists of nuclear receptor subfamily 2, group E, member 3 (NR2E3).

Name: Summary of probe development efforts to identify agonists of nuclear receptor subfamily 2, group E, member 3 (NR2E3). ..more
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AID: 2325
Data Source: The Scripps Research Institute Molecular Screening Center (NR2E3_AG_SUMMARY)
BioAssay Type: Summary, Candidate Probes/Leads with Supporting Evidence
Depositor Category: NIH Molecular Libraries Probe Production Network
BioAssay Version:
Deposit Date: 2010-02-01
Modify Date: 2012-12-06
Target
Related Experiments
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AIDNameTypeComment
2300TR-FRET-based primary biochemical high throughput screening assay to identify agonists of nuclear receptor subfamily 2, group E, member 3 (NR2E3).Screeningdepositor-specified cross reference: Primary screen (NR2E3 agonists in singlicate)
2379TR-FRET-based biochemical high throughput confirmation assay for agonists of nuclear receptor subfamily 2, group E, member 3 (NR2E3)Screeningdepositor-specified cross reference
2758TR-FRET-based biochemical high throughput dose response assay for agonists of nuclear receptor subfamily 2, group E, member 3 (NR2E3)Confirmatorydepositor-specified cross reference
2759Counterscreen for agonists of nuclear receptor subfamily 2, group E, member 3 (NR2E3): TR-FRET-based biochemical high throughput dose response assay to identify agonists of the interaction between peroxisome proliferator-activated receptor gamma (PPARg) and nuclear receptor co-repressor 2 (NCOR2)Confirmatorydepositor-specified cross reference
463256TR-FRET-based biochemical high throughput dose response assay to identify NR2E3 inverse agonistsConfirmatorydepositor-specified cross reference: Dose response (NR2E3 inverse agonists in triplicate)
463257Counterscreen for NR2E3 inverse agonists: TR-FRET-based biochemical high throughput dose response assay to identify inverse agonists of the interaction between peroxisome proliferator-activated receptor gamma (PPARg) and nuclear receptor co-repressor 2 (NCOR2)Confirmatorydepositor-specified cross reference: Dose response counterscreen (PPARg and NCOR2 interaction inverse agonists in triplicate)
504787Counterscreen for agonists of nuclear receptor subfamily 2, group E, member 3 (NR2E3): TR-FRET-based biochemical high throughput assay to identify agonists of the interaction between peroxisome proliferator-activated receptor gamma (PPARg) and nuclear receptor co-repressor 2 (NCOR2)Screeningdepositor-specified cross reference: Counterscreen (PPARg and NCOR2 interaction agonists in triplicate)
602229Luminescence-based cell-based high throughput primary screening assay to identify agonists of nuclear receptor subfamily 2, group E, member 3 (NR2E3)Screeningdepositor-specified cross reference: Primary screen (NR2E3 agonists in singlicate)
624378Luminescence-based cell-based high throughput confirmation assay for agonists of nuclear receptor subfamily 2, group E, member 3 (NR2E3)Screeningdepositor-specified cross reference: Primary screen (NR2E3 agonists in singlicate: Cell-based Assay)
624379Counterscreen for agonists of nuclear receptor subfamily 2, group E, member 3 (NR2E3): Luminescence-based cell-based high throughput screening assay to identify agonists of the Herpes Virus Virion Protein 16 (VP16)Screeningdepositor-specified cross reference: Counterscreen (VP16 modulators in triplicate)
624394Luminescence-based cell-based high throughput dose response assay for agonists of nuclear receptor subfamily 2, group E, member 3 (NR2E3)Confirmatorydepositor-specified cross reference: Dose response (NR2E3 inhibitors in triplicate)
624395Counterscreen for agonists of nuclear receptor subfamily 2, group E, member 3 (NR2E3):Luminescence-based cell-based high throughput dose response assay to identify inhibitors of the Herpes Virus Virion Protein 16 (VP16)Confirmatorydepositor-specified cross reference: Dose response counterscreen (VP16 inhibitors in triplicate)
651846Late Stage Counterscreen for agonists of nuclear receptor subfamily 2, group E, member 3 (NR2E3): Luminescence-based cell-based high throughput dose response screening assay to identify agonists of the Herpes Virus Virion Protein 16 (VP16)Confirmatorydepositor-specified cross reference: Late stage dose response counterscreen (VP16 agonists in triplicate)
651849Late stage Luminescence-based cell-based high throughput dose response assay for agonists of nuclear receptor subfamily 2, group E, member 3 (NR2E3)Confirmatorydepositor-specified cross reference: Late stage dose response (NR2E3 agonists in triplicate)
Description:
Source (MLPCN Center Name): The Scripps Research Institute Molecular Screening Center
Affiliation: The Scripps Research Institute, TSRI
Assay Provider: Konstantin Petrukhin, Columbia University
Network: Molecular Library Probe Production Centers Network (MLPCN)
Grant Proposal Number: 1 R21 NS061718-01 Fast Track
Grant Proposal PI: Konstantin Petrukhin, Columbia University
External Assay ID: NR2E3_AG_SUMMARY

Name: Summary of probe development efforts to identify agonists of nuclear receptor subfamily 2, group E, member 3 (NR2E3).

Description:

Nuclear receptors are small molecule- and hormone-regulated transcription factors with discrete DNA-binding and ligand-binding domains, and are essential during development and for maintenance of proper cell function in adults. Small pharmacological compounds that bind to the cleft of the ligand-binding domain could alter receptor conformation and subsequently modify transcription of target genes. Such ligands (agonists and antagonists) have been designed for 23 nuclear receptors among the 48 identified in the human genome (1-3). NR2E3 is an orphan nuclear receptor expressed exclusively in rod and cone photoreceptor cells of the retina (4-7). In its unliganded state, NR2E3 acts as a transcriptional repressor (4, 8, 9) due to interaction with co-repressors such as retinal RetCOR (10), NCOR (11) or SMRT (11). Defects in this gene are a cause of several retinopathies (12-15). Studies showing that mice with a spontaneous deletion in the Nr2e3 gene develop late-onset, progressive retinal degeneration (7), suggest that this nuclear receptor is essential for photoreceptor development and survival. The identification of selective NR2E3 agonists would provide useful tools for the understanding of the biological role of NR2E3 in retinal diseases.

Summary of Probe Development Effort:

This probe development effort is focused on the identification of NR2E3 agonists (AID 2300). All AIDs that contain results associated with this project can be found in the "Related Bioassays" section of this Summary AID.

References:

1. Evans, R.M., The nuclear receptor superfamily: a rosetta stone for physiology. Mol Endocrinol, 2005. 19(6): p. 1429-38.
2. Kliewer, S.A., Lehmann, J.M., and Willson, T.M., Orphan nuclear receptors: shifting endocrinology into reverse. Science, 1999. 284(5415): p. 757-60.
3. Li, Y., Lambert, M.H., and Xu, H.E., Activation of nuclear receptors: a perspective from structural genomics. Structure, 2003. 11(7): p. 741-6.
4. Chen, J., Rattner, A., and Nathans, J., The rod photoreceptor-specific nuclear receptor Nr2e3 represses transcription of multiple cone-specific genes. J Neurosci, 2005. 25(1): p. 118-29.
5. Cheng, H., Khanna, H., Oh, E.C., Hicks, D., Mitton, K.P., and Swaroop, A., Photoreceptor-specific nuclear receptor NR2E3 functions as a transcriptional activator in rod photoreceptors. Hum Mol Genet, 2004. 13(15): p. 1563-75.
6. Haider, N.B., Naggert, J.K., and Nishina, P.M., Excess cone cell proliferation due to lack of a functional NR2E3 causes retinal dysplasia and degeneration in rd7/rd7 mice. Hum Mol Genet, 2001. 10(16): p. 1619-26.
7. Akhmedov, N.B., Piriev, N.I., Chang, B., Rapoport, A.L., Hawes, N.L., Nishina, P.M., Nusinowitz, S., Heckenlively, J.R., Roderick, T.H., Kozak, C.A., Danciger, M., Davisson, M.T., and Farber, D.B., A deletion in a photoreceptor-specific nuclear receptor mRNA causes retinal degeneration in the rd7 mouse. Proc Natl Acad Sci U S A, 2000. 97(10): p. 5551-6.
8. Gerber, S., Rozet, J.M., Takezawa, S.I., dos Santos, L.C., Lopes, L., Gribouval, O., Penet, C., Perrault, I., Ducroq, D., Souied, E., Jeanpierre, M., Romana, S., Frezal, J., Ferraz, F., Yu-Umesono, R., Munnich, A., and Kaplan, J., The photoreceptor cell-specific nuclear receptor gene (PNR) accounts for retinitis pigmentosa in the Crypto-Jews from Portugal (Marranos), survivors from the Spanish Inquisition. Hum Genet, 2000. 107(3): p. 276-84.
9. Kobayashi, M., Hara, K., Yu, R.T., and Yasuda, K., Expression and functional analysis of Nr2e3, a photoreceptor-specific nuclear receptor, suggest common mechanisms in retinal development between avians and mammals. Dev Genes Evol, 2008. 218(8): p. 439-44.
10. Takezawa, S., Yokoyama, A., Okada, M., Fujiki, R., Iriyama, A., Yanagi, Y., Ito, H., Takada, I., Kishimoto, M., Miyajima, A., Takeyama, K., Umesono, K., Kitagawa, H., and Kato, S., A cell cycle-dependent co-repressor mediates photoreceptor cell-specific nuclear receptor function. EMBO J, 2007. 26(3): p. 764-74.
11. Kapitskaya, M., Cunningham, M.E., Lacson, R., Kornienko, O., Bednar, B., and Petrukhin, K., Development of the high throughput screening assay for identification of agonists of an orphan nuclear receptor. Assay Drug Dev Technol, 2006. 4(3): p. 253-62.
12. Bernal, S., Solans, T., Gamundi, M.J., Hernan, I., de Jorge, L., Carballo, M., Navarro, R., Tizzano, E., Ayuso, C., and Baiget, M., Analysis of the involvement of the NR2E3 gene in autosomal recessive retinal dystrophies. Clin Genet, 2008. 73(4): p. 360-6.
13. Coppieters, F., Leroy, B.P., Beysen, D., Hellemans, J., De Bosscher, K., Haegeman, G., Robberecht, K., Wuyts, W., Coucke, P.J., and De Baere, E., Recurrent mutation in the first zinc finger of the orphan nuclear receptor NR2E3 causes autosomal dominant retinitis pigmentosa. Am J Hum Genet, 2007. 81(1): p. 147-57.
14. Gire, A.I., Sullivan, L.S., Bowne, S.J., Birch, D.G., Hughbanks-Wheaton, D., Heckenlively, J.R., and Daiger, S.P., The Gly56Arg mutation in NR2E3 accounts for 1-2% of autosomal dominant retinitis pigmentosa. Mol Vis, 2007. 13: p. 1970-5.
15. Sharon, D., Sandberg, M.A., Caruso, R.C., Berson, E.L., and Dryja, T.P., Shared mutations in NR2E3 in enhanced S-cone syndrome, Goldmann-Favre syndrome, and many cases of clumped pigmentary retinal degeneration. Arch Ophthalmol, 2003. 121(9): p. 1316-23.

Keywords:

Summary, summary AID, nuclear receptor subfamily 2, group E, member 3, NR2E3; RetCOR, corepressor, photoreceptor-specific nuclear receptor; PNR, blindness, age-related macular degeneration, AMD, primary, primary screen, orphan nuclear receptor, fluorescence, TR-FRET, agonist, activator, HTS, 1536, Scripps, Scripps Florida, Research Institute Molecular Screening Center, SRIMSC, Molecular Libraries Probe Production Centers Network, MLPCN.
Comment
A probe development effort is underway.
Additional Information
Grant Number: 1 R21 NS061718-01

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