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BioAssay: AID 652133

Summary of the probe development effort to identify activators of the DAF-12 from the parasite S. stercoralis (ssDAF-12)

Name: Summary of the probe development effort to identify activators of the DAF-12 from the parasite S. stercoralis (ssDAF-12). ..more
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AID: 652133
Data Source: The Scripps Research Institute Molecular Screening Center (SSDAF12_AG_SUMMARY)
BioAssay Type: Summary, Candidate Probes/Leads with Supporting Evidence
Depositor Category: NIH Molecular Libraries Probe Production Network
BioAssay Version:
Deposit Date: 2013-03-19
Modify Date: 2013-06-11
Target
Depositor Specified Assays
AIDNameTypeComment
652126Luminescence-based cell-based primary high throughput screening assay to identify activators of the DAF-12 from the parasite S. stercoralis (ssDAF-12)screeningPrimary screen (ssDAF-12 activators in singlicate)
720734Luminescence-based cell-based high throughput dose response assay to identify activators of the DAF-12 from the parasite S. stercoralis (ssDAF-12)confirmatory
720737Counterscreen for agonists of the daf-12 abnormal Dauer Formation: Luminescence-based cell-based screening assay to identify agonists of the Liver-X-Receptor (LXR).confirmatory
Description:
Source (MLPCN Center Name): The Scripps Research Institute Molecular Screening Center
Affiliation: UT Southwestern
Assay Provider: David Mangelsdorf, UT Southwestern
Network: Molecular Library Probe Production Centers Network (MLPCN)
Grant Proposal Number: U19 DK062434
Grant Proposal Pi: David Mangelsdorf, UT Southwestern
External Assay ID: SSDAF12_AG_SUMMARY

Name: Summary of the probe development effort to identify activators of the DAF-12 from the parasite S. stercoralis (ssDAF-12).

Description:

Parasitic helminthes (worms) are a significant health and economic burden: over two billion people are infected by helminthes [1], and parasitic nematodes cause billions of dollars of crop damage each year in the United States [2]. The developmental stages of these organisms are widely studied [3, 4]. One stage, dauer (German for "duration," also known as an alternative L3 larval stage) covers an alternative larval stage in which development stops and the worms enter a hibernation-like state in which they can survive extremely harsh environmental conditions, often for years. In the case of parasitic nematodes, this resting state is quite often the infectious state [5]. As the burden of parasitic nematodes grows in the face of emerging resistance to the few existing antihelminthic agents, it is becoming increasingly important to understand the life cycles of parasitic worms so that new drugs may be developed [1]. The nuclear receptor DAF-12 (for "dauer formation"), first identified in C. elegans, is known to control many nematode species' entry into and exit from the dauer resting state [6]. Daf-12 belongs to a family of over 30 genes which transduce environmental signals to influence the choice between dauer or reproductive development. Favorable environments activate insulin/IGF and TGF-beta pathways converge, leading to production of the steroid hormone dafachronic acid (DA), which binds and activates Daf-12 [7]. Currently available antihelminthic agents, to which resistance is beginning to emerge, act primarily on the feeding stages of the worms and have little effect on the infectious stages [8]. Therefore, pharmacologic activators developed through high-throughput screening would be used both practically as nematicides and academically as tools to characterize the role of DAF-12 in modulating life cycle [8, 9].

Summary of Probe Development Effort:

This probe development effort is focused on the identification of activators of the DAF-12 from the parasite S. stercoralis (ssDAF-12). All AIDs that contain results associated with this project can be found in the "Related Bioassays" section of this Summary AID.

References:

1. Jasmer, D.P., A. Goverse, and G. Smant, Parasitic nematode interactions with mammals and plants. Annu Rev Phytopathol, 2003. 41: p. 245-70.
2. Hotez, P.J., J. Bethony, M.E. Bottazzi, S. Brooker, D. Diemert, and A. Loukas, New technologies for the control of human hookworm infection. Trends Parasitol, 2006. 22(7): p. 327-31
3. Mooijaart, S.P., B.W. Brandt, E.A. Baldal, J. Pijpe, M. Kuningas, M. Beekman, B.J. Zwaan, P.E. Slagboom, R.G. Westendorp, and D. van Heemst, C. elegans DAF-12, Nuclear Hormone Receptors and human longevity and disease at old age. Aging Res Rev, 2005. 4(3): p. 351-71
4. Brenner, S., The genetics of Caenorhabditis elegans. Genetics, 1974. 77(1): p. 71-94
5. Motola, D.L., C.L. Cummins, V. Rottiers, K.K. Sharma, T. Li, Y. Li, K. Suino-Powell, H.E. Xu, R.J. Auchus, A. Antebi, and D.J. Mangelsdorf, Identification of ligands for DAF-12 that govern dauer formation and reproduction in C. elegans. Cell, 2006. 124(6): p. 1209-23
6. Antebi, A., W.H. Yeh, D. Tait, E.M. Hedgecock, and D.L. Riddle, daf-12 encodes a nuclear receptor that regulates the dauer diapause and developmental age in C. elegans. Genes Dev, 2000. 14(12): p. 1512-27.
7. Gerisch, B. and A. Antebi, Hormonal signals produced by DAF-9/cytochrome P450 regulate C. elegans dauer diapause in response to environmental cues. Development, 2004. 131(8): p. 1765-76.
8. Wang, Z., X.E. Zhou, D.L. Motola, X. Gao, K. Suino-Powell, A. Conneely, C. Ogata, K.K. Sharma, R.J. Auchus, J.B. Lok, J.M. Hawdon, S.A. Kliewer, H.E. Xu, and D.J. Mangelsdorf, Identification of the nuclear receptor DAF-12 as a therapeutic target in parasitic nematodes. Proc Natl Acad Sci U S A, 2009. 106(23): p. 9138-43
9. Schroeder, F.C., Small molecule signaling in Caenorhabditis elegans. ACS Chem Biol, 2006. 1(4): p. 198-200.

Keywords:

Summary, Summary AID, ssDAF12, daf12, daf-12, S. stercoralis, Caenorhabditis elegans, C. elegans, lumi, luminescence, HTS, high throughput screen, 1536, Scripps Florida, The Scripps Research Institute Molecular Screening Center, SRIMSC, Molecular Libraries Probe Production Centers Network, MLPCN.
Protocol
Comment
In the absence of a Protein Entry for the DAF-12 protein from S. stercoralis in NCBI's database, links to the target sequence and origin refer to the closest known orthologue from the prototypic parasitic helminth C.elegans.
Additional Information
Grant Number: U19 DK062434

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