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  • 1
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    Systems survey of endocytosis by multiparametric image analysis (2010)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2010-03-02
    Description: Endocytosis is a complex process fulfilling many cellular and developmental functions. Understanding how it is regulated and integrated with other cellular processes requires a comprehensive analysis of its molecular constituents and general design principles. Here, we developed a new strategy to phenotypically profile the human genome with respect to transferrin (TF) and epidermal growth factor (EGF) endocytosis by combining RNA interference, automated high-resolution confocal microscopy, quantitative multiparametric image analysis and high-performance computing. We identified several novel components of endocytic trafficking, including genes implicated in human diseases. We found that signalling pathways such as Wnt, integrin/cell adhesion, transforming growth factor (TGF)-beta and Notch regulate the endocytic system, and identified new genes involved in cargo sorting to a subset of signalling endosomes. A systems analysis by Bayesian networks further showed that the number, size, concentration of cargo and intracellular position of endosomes are not determined randomly but are subject to specific regulation, thus uncovering novel properties of the endocytic system.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Collinet, Claudio -- Stoter, Martin -- Bradshaw, Charles R -- Samusik, Nikolay -- Rink, Jochen C -- Kenski, Denise -- Habermann, Bianca -- Buchholz, Frank -- Henschel, Robert -- Mueller, Matthias S -- Nagel, Wolfgang E -- Fava, Eugenio -- Kalaidzidis, Yannis -- Zerial, Marino -- England -- Nature. 2010 Mar 11;464(7286):243-9. doi: 10.1038/nature08779. Epub 2010 Feb 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Max Planck Institute for Molecular Cell Biology and Genetics, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20190736" target="_blank"〉PubMed〈/a〉
    Keywords: Computing Methodologies ; Endocytosis/*physiology ; Endosomes/metabolism ; Epidermal Growth Factor/metabolism ; Gene Expression Profiling/*methods ; Genome-Wide Association Study ; Humans ; *Image Processing, Computer-Assisted ; Metabolic Networks and Pathways/physiology ; Microscopy, Confocal ; Phenotype ; Protein Transport/physiology ; RNA Interference ; Signal Transduction/physiology ; Transferrin/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    Identification of siRNA delivery enhancers by a chemical library screen (2015)
    Oxford University Press
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    Publication Date: 2015-09-19
    Description: Most delivery systems for small interfering RNA therapeutics depend on endocytosis and release from endo-lysosomal compartments. One approach to improve delivery is to identify small molecules enhancing these steps. It is unclear to what extent such enhancers can be universally applied to different delivery systems and cell types. Here, we performed a compound library screen on two well-established siRNA delivery systems, lipid nanoparticles and cholesterol conjugated-siRNAs. We identified fifty-one enhancers improving gene silencing 2–5 fold. Strikingly, most enhancers displayed specificity for one delivery system only. By a combination of quantitative fluorescence and electron microscopy we found that the enhancers substantially differed in their mechanism of action, increasing either endocytic uptake or release of siRNAs from endosomes. Furthermore, they acted either on the delivery system itself or the cell, by modulating the endocytic system via distinct mechanisms. Interestingly, several compounds displayed activity on different cell types. As proof of principle, we showed that one compound enhanced siRNA delivery in primary endothelial cells in vitro and in the endocardium in the mouse heart. This study suggests that a pharmacological approach can improve the delivery of siRNAs in a system-specific fashion, by exploiting distinct mechanisms and acting upon multiple cell types.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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