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Multi-Transgenic Pigs for Xenotransplantation

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Multi-Transgenic Pigs for Xenotransplantation Fakultät Wissenschaftszentrum Weihenstephan für Ernährung, Landnutzung und Umwelt Lehrstuhl für Biotechnologie der Nutztiere Multi-transgenic pigs for xenotransplantation Konrad Josef Fischer Vollständiger Abdruck der von der Fakultät Wissenschaftszentrum Weihenstephan für Ernährung, Landnutzung und Umwelt der Technischen Universität München zur Erlangung des akademischen Grades eines Doktors der Naturwissenschaften genehmigten Dissertation. Vorsitzender: Prof. Dr. Siegfried Scherer Prüfer der Dissertation: 1. Prof. Angelika Schnieke, Ph.D. 2. Prof. Dr. Eckhard Wolf Ludwig-Maximilians-Universität München 3. Prof. Dr. Jochen Seißler Ludwig-Maximilians-Universität München Die Dissertation wurde am 15.02.2016 bei der Technischen Universität München eingereicht und durch die Fakultät Wissenschaftszentrum Weihenstephan für Ernährung, Landnutzung und Umwelt am 21.06.2016 angenommen. Inhalt Abstract ................................................................................................................................................ 6 Zusammenfassung ........................................................................................................................... 8 1. Introduction ............................................................................................................................... 10 1.1 Xenotransplantation ........................................................................................................ 10 1.2 Hyperacute Rejection ...................................................................................................... 11 1.3 Acute vascular and acute humoral xenograft rejection ..................................... 13 1.4 Complement regulators .................................................................................................. 14 1.4.1 CD46 .............................................................................................................................. 15 1.4.2 CD55 .............................................................................................................................. 16 1.4.3 CD59 .............................................................................................................................. 17 1.5 Antithrombotic genes ...................................................................................................... 18 1.6 Endothelium protective genes ..................................................................................... 20 1.6.1 Heme oxygenase 1.................................................................................................... 20 1.6.2 A20 ................................................................................................................................. 22 1.7 Immune regulatory genes and cell mediated xenograft rejection ................. 24 1.7.1 NK cells ......................................................................................................................... 24 1.7.2 Macrophages .............................................................................................................. 25 1.7.3 T-cells ............................................................................................................................ 26 1.8 BAC and PAC vectors ....................................................................................................... 27 1.9 Human artificial chromosomes and MMCT ............................................................ 28 1.10 Genetic modifications in livestock ........................................................................... 30 1.10.1 Transgenic livestock ............................................................................................. 30 1.10.2 Precise genetic modifications ........................................................................... 31 1.11 Porcine ROSA26 ............................................................................................................... 34 1.12 Project goals ..................................................................................................................... 35 2. Materials and Methods ........................................................................................................... 36 2.1Chemicals .............................................................................................................................. 36 2.2 Enzymes ............................................................................................................................... 37 2.3 Antibodies ............................................................................................................................ 38 2.4 Kits .......................................................................................................................................... 38 2.5 Cells ........................................................................................................................................ 39 2.5.1 Bacterial strains ........................................................................................................ 39 2.5.2 Eukaryotic cell lines ................................................................................................ 39 2.6 Primers ................................................................................................................................. 39 2.7 qPCR probes ........................................................................................................................ 40 2 2.8 Ladders ................................................................................................................................. 40 2.9 Vectors .................................................................................................................................. 40 2.9.1 Bacterial Artificial Chromosomes ...................................................................... 40 2.9.2 Plasmids ....................................................................................................................... 40 2.10 Tissue culture media and supplements ................................................................. 41 2.11 Bacterial buffers and supplements.......................................................................... 41 2.12 Buffers and solutions .................................................................................................... 41 2.13 Laboratory equipment ................................................................................................. 43 2.14 Consumables .................................................................................................................... 45 2.15 Software ............................................................................................................................. 46 2.16 Glycerol stocks of bacteria .......................................................................................... 46 2.17 Isolation of plasmid DNA............................................................................................. 46 2.17.1 Miniprep .................................................................................................................... 46 2.17.2 Midiprep and Maxiprep ....................................................................................... 47 2.18 Recombineering competent SW106 ....................................................................... 47 2.19 DNA restriction digest .................................................................................................. 48 2.20 Blunting of DNA fragments......................................................................................... 48 2.21 Dephosphorylation of cleaved DNA ........................................................................ 49 2.22 Ligation .............................................................................................................................. 49 2.23 Electroporation ............................................................................................................... 49 2.24 Colony PCR ........................................................................................................................ 50 2.25 Agarose gel electrophoresis ....................................................................................... 50 2.26 Pulsed field gel electrophoresis ................................................................................ 50 2.27 Isolation of DNA fragments from agarose-gels ................................................... 51 2.28 Determination of DNA and RNA concentration .................................................. 51 2.29 Polymerase chain reaction (PCR) ............................................................................ 51 2.30 Splice Overlap Extension PCR (SOE-PCR) ............................................................ 52 2.31 Sequencing ........................................................................................................................ 53 2.32 Microcell-mediated chromosome transfer........................................................... 53 2.33 Fluorescence in situ hybridization .......................................................................... 54 2.33.1 Preparation of metaphase chromosome spreads ..................................... 54 2.33.2 Probe production ................................................................................................... 55 2.33.3 Probes for FISH ......................................................................................................
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