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Abstract
ATP-binding cassette (ABC) transporters such as ABCB1 (P-glycoprotein), ABCC1 (MRP1), and ABCG2 (BCRP) are well known for their role in rendering cancer cells resistant to chemotherapy. Additionally, recent research provided evidence that, along with other ABC transporters (ABCA1 and ABCA7), they might be cornerstones to tackle neurodegenerative diseases. Overcoming chemoresistance in cancer, understanding drug-drug interactions, and developing efficient and specific drugs that alter ABC transporter function are hindered by a lack of in vivo research models, which are fully predictive for humans. Hence, the humanization of ABC transporters in mice has become a major focus in pharmaceutical and neurodegenerative research. Here, we present a characterization of the first Abcc1 humanized mouse line. To preserve endogenous expression profiles, we chose to generate a knockin mouse model that leads to the expression of a chimeric protein that is fully human except for one amino acid. We found robust mRNA and protein expression within all major organs analyzed (brain, lung, spleen, and kidney). Furthermore, we demonstrate the functionality of the expressed human ABCC1 protein in brain and lungs using functional positron emission tomography imaging in vivo. Through the introduction of loxP sites, we additionally enabled this humanized mouse model for highly sophisticated studies involving cell type–specific transporter ablation. Based on our data, the presented mouse model appears to be a promising tool for the investigation of cell-specific ABCC1 function. It can provide a new basis for better translation of preclinical research.
Footnotes
- Received January 23, 2019.
- Accepted June 3, 2019.
↵1 Current affiliation: Institute for Experimental and Clinical Pharmacology and Toxicology, Center of Brain, Behavior and Metabolism, University of Lübeck, Lübeck, Germany.
The establishment of the mice was financially supported by Immungenetics AG (Rostock, Germany). The mice are available to researchers at nonprofit organizations without restrictions against a one-time contribution to help maintaining the strain. The work of J.P. was financed by Deutsche Forschungsgemeinschaft/Germany [Grants PA930/9 and PA930/12]; Wirtschaftsministerium Sachsen-Anhalt/Germany [Grant ZS/2016/05/78617]; the Leibniz Association, Leibniz-Wettbewerb [Grant SAW-2015-IPB-2]; Latvian Council of Science/Latvia [Grant lzp-2018/1-0275]; HelseSØ/Norway [Grants 2016062, 2019054, and 2019055]; Norsk Forskningsrådet/Norway [Grants 251290 (FRIMEDBIO) and 260786 (PROP-AD)]; and Horizon 2020/European Union [Grant 643417 PROP-AD]. The work of O.L. and T.W. was financed by the Austrian Science Fund [Grant I 1609-B24 (to O.L.)], and the Lower Austria Corporation for Research and Education [Grant LS14-008 (to T.W.)]. PROP-AD is a European Union Joint Programme–Neurodegenerative Disease Research (JPND) project. The project is supported through the following funding organizations under the aegis of JPND [www.jpnd.eu; (Academy of Finland [AKA] Grant 301228 (Finland), Bundesministerium fur Bildung ünd Forschung [BMBF] Grant 01ED1605 (Germany), Chief Scientific Office of the Israeli Ministry [CSO-MOH] Grant 30000-12631 (Israel), Norges Forskningsradet/Norwegian Research Council [NFR] Grant 260786 (Norway), and Swedish Research Council [SRC] Grant 2015-06795 (Sweden)]. This project has received funding from the European Union’s Horizon 2020 research and innovation program [Grant 643417 (JPco-fuND, co-funded initiative between JPND and the European Commission)].
J.P. is shareholder of Immungenetics AG.
↵This article has supplemental material available at molpharm.aspetjournals.org.
- Copyright © 2019 by The Author(s)
This is an open access article distributed under the CC BY-NC Attribution 4.0 International license.