Summary of the probe development effort to identify activators of the DAF-12 from the parasite H. contortus (hcDAF-12)
Name: Summary of the probe development effort to identify activators of the DAF-12 from the parasite H. contortus (hcDAF-12). ..more
Source (MLPCN Center Name): The Scripps Research Institute Molecular Screening Center (SRIMSC)
Affiliation: The Scripps Research Institute, TSRI
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: HCDAF12_AG_SUMMARY
Name: Summary of the probe development effort to identify activators of the DAF-12 from the parasite H. contortus (hcDAF-12).
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).
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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. Ageing 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.
Summary, Summary AID, daf12, daf-12, Caenorhabditis elegans, C. elegans, primary screen, primary, PRUN, lumi, luminescence, HTS, high throughput screen, 1536, Scripps Florida, The Scripps Research Institute Molecular Screening Center, SRIMSC, Molecular Libraries Probe Production Centers Network, MLPCN.
In the absence of a Protein Entry for the DAF-12 protein from H.contortus in NCBI's database, links to the target sequence and origin refer to the closest known orthologue from the prototypic parasitic helminth C.elegans.