Identification and characterization of novel Fasciola hepatica sodium chloride dependent taurine transporter
Başlık çevirisi mevcut değil.
- Tez No: 508200
- Danışmanlar: Dr. OLIVER KUDLACEK, Prof. Dr. MICHAEL FREISSMUTH
- Tez Türü: Doktora
- Konular: Eczacılık ve Farmakoloji, Pharmacy and Pharmacology
- Anahtar Kelimeler: Belirtilmemiş.
- Yıl: 2018
- Dil: İngilizce
- Üniversite: Medical University of Vienna
- Enstitü: Yurtdışı Enstitü
- Ana Bilim Dalı: Belirtilmemiş.
- Bilim Dalı: Belirtilmemiş.
- Sayfa Sayısı: 106
Özet
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Özet (Çeviri)
The economic burden imposed by the liver fluke Fasciola hepatica is the result of its infestation of domestic ruminants. The fact that several million people worldwide are infested by this trematode has led the World Health Organization (WHO) to classify human fascioliasis as a disease of vital global public health importance. Because a vaccine against this parasite is not available anthelmintic drugs are the only option, for both animals and people. As an anthelminthic chemotherapeutic, triclabendazole has been the drug of choice in fighting this parasite for more than 25 years. Triclabendazole is active against both adult and juvenile flukes and is well tolerated by the host organisms. However, the increasing prevalence of flukes resistant to triclabendazole has made the identification of alternative drug targets a priority. In this study, I focused on the fact that adult F. hepatica persists in the hostile environment of the bile ducts of infected organisms. In mammals, bile acids are rendered less toxic by conjugation to taurine (2-aminoethanesulfonic acid). This reaction is thus also contingent on cellular uptake of taurine. In my thesis, I cloned the Fasciola hepatica taurine transporter, a member of the solute carrier-6 (SLC6) family. A comparative analysis of the sequence indicated its close relation to unknown SLC6 transporters from related nematodes (i.e., Clonorchis sinensis and Schistosoma spp.) analysis When heterologously expressed in HEK293 cells, this F. hepatica transporter supported the high-affinity cellular uptake of taurine (KM=12.0 ± 0.5 μM) but not of GABA. Substrate uptake was dependent on Na+- and Cl- (calculated stoichiometry 2:1). Consistent with the low chloride concentration in mammalian bile, the F. hepatica transporter had a higher apparent affinity for Cl- (EC50 =14±3 mM) than the human taurine transporter (EC50=55±7 mM). I incubated flukes with unconjugated bile acids in the presence and absence of taurine and found that taurine promoted the survival of flukes, while the taurine transporter inhibitor guanidinoethansulfonic acid abolished this protective effect of taurine. These observations support the conclusion that the taurine transporter is critical for the survival of liver flukes in the bile. Thus, the taurine transporter represents a viable drug target candidate.
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