Dokument: Myelinating CNS-cultures as a new model for the brain-/CNS-immune interface
| Titel: | Myelinating CNS-cultures as a new model for the brain-/CNS-immune interface | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=70025 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20250709-130313-9 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Deutsch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Brauweiler, Marcel [Autor] | |||||||
| Dateien: |
| |||||||
| Beitragende: | Prof. Dr. Goebels, Norbert [Gutachter] Prof. Dr. von Gall, Charlotte [Gutachter] | |||||||
| Stichwörter: | Rückenmarkskulturen, spinal cord culture, LINGO-1 | |||||||
| Dewey Dezimal-Klassifikation: | 600 Technik, Medizin, angewandte Wissenschaften » 610 Medizin und Gesundheit | |||||||
| Beschreibungen: | Zusammenfassung
Die Myelinisierung von Axonen ist essenziell für die Funktionsweise des menschlichen Nervensystems. Die Multiple Sklerose (MS) als chronisch-entzündliche ZNS-Erkrankung führt zur Demyelinisierung von Axonen und bei ausbleibender Regeneration zum sekundären Untergang der Neurone. Zum Verständnis der Pathophysiologie sowie zur Entwicklung von neuen Therapiestrategien sind Myelinisierungsmechanismen Gegenstand der MS-Forschung. Diese stützt sich größtenteils auf das Tiermodell der experimentellen autoimmunen Enzephalomyelitis (EAE). Im Gegensatz dazu bietet das Modell der myelinisierenden Rückenmarkskultur (spinal cord culture, SCC) bei deutlich reduzierter Anzahl an Versuchstieren und geringerem Tierleid die Möglichkeit zur gezielteren Untersuchung potenzieller Therapeutika. Das Protein LINGO-1 (leucine-rich repeat and Ig-like domain-containing Nogo receptor interacting protein 1) gilt als Inhibitor des Neuritenwachstums, der Oligodendrozyten- Differenzierung und der Myelinisierung. Damit stellt LINGO-1 ein Target für alternative Therapieansätze bei MS dar. Ziel der Arbeit ist die Etablierung eines Hochdurchsatzverfahrens zum Screening potenziell promyeliniserender Substanzen auf Basis von SCCs. Zu diesem Zweck wurden die anti-LINGO- 1 Antikörper 1A7, Li03 und Li81 (patentiert von Biogen) eingesetzt. SCCs wurden aus dem Rückenmark von 13,5 Tage alten Mäuseembryonen gewonnen und für 21 bzw. 30 Tage im Mikrotiter-Format kultiviert. Innerhalb der ersten Woche bildete sich das neuronale Netzwerk aus. Nach 14 Tagen in Kultur setzte die Myelinisierung der Axone ein und erreichte ihr Maximum in den Wochen 3-4. An Tag 7 in Kultur startete die Behandlung der SCCs mit den anti-LINGO- 1 Antikörpern. Als Positivkontrolle für eine gesteigerte Myelinisierung diente das Schilddrüsenhormon Triiodthyronin (T3). Nach 14 Tagen Behandlung wurden die Zellkulturen fixiert und Zellkerne, Neurofilament sowie Myelin immunhistochemisch angefärbt. In Zusammenarbeit mit Hoffmann-La Roche erfolgte die Quantifizierung der Myelinisierung. Li03 und Li81 (10 μg/ml) zeigten im Vergleich zur Lösemittelkontrolle eine relative Verstärkung der Myelinisierung um mehr als 40% (p < 0,05). Li81 steigerte auch die Dichte des neuronalen Netzwerkes signifikant. Der Einsatz von 1A7 (10 μg/ml), Li03 und Li81 (jeweils 30 μg/ml) förderten zwar die Myelinisierung, allerdings waren die Unterschiede zur Lösemittelkontrolle nicht statistisch signifikant (p > 0,05). Für 1A7 in 30 μg/ml konnte sogar eine Abnahme der Myelinisierung beobachtet werden (allerdings p > 0,05). Die anti-LINGO-1 Antikörper bewirkten eine Verstärkung der primären Myelinisierung. Hierbei zeigte sich keine lineare Dosis-Wirkungs-Beziehung. Das SCC-Modell eignet sich für Hochdurchsatz-Screenings und stellt unter ökonomischen und ethischen Gesichtspunkten eine sinnvolle Ergänzung zum EAE-Modell dar. Zur Etablierung eines ergänzenden MSVersuchsmodell ist die Entwicklung eines De- und Remyelinisierungsverfahrens geplant.Summary The myelination of axons is very important for the functionality of the human nervous system. Multiple sclerosis (MS) as a chronic-inflammatory CNS-disease leads to demyelination and secondary loss of axons, if remyelination fails. The MS-research deals with processes of myelination for better understanding of MS-pathophysiology and development of new therapeutic strategies. It is mainly based on the model of experimental autoimmune encephalomyelitis (EAE). In contrast, the model of myelinating spinal cord culture (SCC) needs less laboratory animals and causes less animal suffering but offers the opportunity of testing a great number of potential therapeutics. The protein LINGO-1 (leucine-rich repeat and Ig-like domain-containing Nogo receptor interacting protein 1) inhibits neurite outgrowth, differentiation of oligodendrocytes and myelination. LINGO-1 might be a target for alternative therapeutic approaches for MS. Aim of the study is the development of a high throughput system to investigate the potential promoting myelination of different substances. Therefore, we used the antagonistic LINGO-1 antibodies 1A7, Li03 and Li81 (patented by Biogen). We prepared spinal cords from 13,5 days old murine embryos. The spinal cord cells were cultivated on microplates for 21 or 30 days. During the first week SCCs formed a dense neuronal network. After 14 days in vitro myelination started and reached its peak around week 3 and 4. At day in vitro (DIV) 7 we started the treatment with the anti-LINGO-1 antibodies. The thyroid hormone T3 was used as positive control for increased myelination. At DIV 21 cells were fixed and cell bodies, neurofilament as well as myelin were stained immunohistochemically. In corporation with the company Hoffmann-La Roche we quantified the extent of myelination. The Li03- and Li81-treatment (10 μg/ml) led, in comparison to the solvent control, to a 40% stronger myelination (p < 0,05). Moreover, Li81 increased the density of neuronal network significantly. The use of 1A7 (10 μg/ml) and Li03 as well as Li81 (both 30 μg/ml) also promoted myelination but differences did not reach statistical significance (p > 0,05). The high dose treatment with 1A7 even decreased the extent of myelination (p > 0,05). The use of anti-LINGO-1 antibodies increased the (primary) myelination significantly. We could show that there was no linear dose-effect relationship. In an economic and ethical point of view SCCs can support the EAE-model as a high throughput screening system. The development of a de- and remyelination assay is required to optimize our process for further MS-research. | |||||||
| Quelle: | Literatur- und Quellenverzeichnis
ALVAREZ, J. I., CAYROL, R. & PRAT, A. 2011. Disruption of central nervous system barriers in multiple sclerosis. Biochim Biophys Acta, 1812, 252-64. BARATEIRO, A. & FERNANDES, A. 2014. Temporal oligodendrocyte lineage progression: in vitro models of proliferation, differentiation and myelination. Biochim Biophys Acta, 1843, 1917-29. BARRES, B. A., LAZAR, M. A. & RAFF, M. C. 1994. A novel role for thyroid hormone, glucocorticoids and retinoic acid in timing oligodendrocyte development. Development, 120, 1097-108. BATES, D. 2011. Treatment effects of immunomodulatory therapies at different stages of multiple sclerosis in short-term trials. Neurology, 76, S14-25. BILLON, N., TOKUMOTO, Y., FORREST, D. & RAFF, M. 2001. Role of thyroid hormone receptors in timing oligodendrocyte differentiation. Dev Biol, 235, 110-20. BLAKEMORE, W. F. 1974. Pattern of remyelination in the CNS. Nature, 249, 577-578. BOURIKAS, D., MIR, A. & WALMSLEY, A. R. 2010. LINGO-1-mediated inhibition of oligodendrocyte differentiation does not require the leucine-rich repeats and is reversed by p75(NTR) antagonists. Mol Cell Neurosci, 45, 363-9. BUCHSER, W., COLLINS, M., GARYANTES, T., GUHA, R., HANEY, S., LEMMON, V., LI, Z. & TRASK, O. J. 2004. Assay Development Guidelines for Image-Based High Content Screening, High Content Analysis and High Content Imaging. In: MARKOSSIAN, S., GROSSMAN, A., BRIMACOMBE, K., ARKIN, M., AULD, D., AUSTIN, C. P., BAELL, J., CHUNG, T. D. Y., COUSSENS, N. P., DAHLIN, J. L., DEVANARAYAN, V., FOLEY, T. L., GLICKSMAN, M., HALL, M. D., HAAS, J. V., HOARE, S. R. J., INGLESE, J., IVERSEN, P. W., KALES, S. C., LAL-NAG, M., LI, Z., MCGEE, J., MCMANUS, O., RISS, T., SARADJIAN, P., SITTAMPALAM, G. S., TARSELLI, M., TRASK, O. J., JR., WANG, Y., WEIDNER, J. R., WILDEY, M. J., WILSON, K., XIA, M. & XU, X. (eds.) Assay Guidance Manual. Bethesda (MD): Eli Lilly & Company and the National Center for Advancing Translational Sciences. CADAVID, D., MELLION, M., HUPPERTS, R., EDWARDS, K. R., CALABRESI, P. A., DRULOVIĆ, J., GIOVANNONI, G., HARTUNG, H. P., ARNOLD, D. L., FISHER, E., RUDICK, R., MI, S., CHAI, Y., LI, J., ZHANG, Y., CHENG, W., XU, L., ZHU, B., GREEN, S. M., CHANG, I., DEYKIN, A. & SHEIKH, S. I. 2019. Safety and efficacy of opicinumab in patients with relapsing multiple sclerosis (SYNERGY): a randomised, placebo-controlled, phase 2 trial. Lancet Neurol, 18, 845-856. CASACCIA-BONNEFIL, P., CARTER, B. D., DOBROWSKY, R. T. & CHAO, M. V. 1996. Death of oligodendrocytes mediated by the interaction of nerve growth factor with its receptor p75. Nature, 383, 716-9. CHANG, A., NISHIYAMA, A., PETERSON, J., PRINEAS, J. & TRAPP, B. D. 2000. NG2- positive oligodendrocyte progenitor cells in adult human brain and multiple sclerosis lesions. J Neurosci, 20, 6404-12. CHAPMAN, B. S. 1995. A region of the 75 kDa neurotrophin receptor homologous to the death domains of TNFR-I and Fas. FEBS Lett, 374, 216-20. CHONG, S. Y., ROSENBERG, S. S., FANCY, S. P., ZHAO, C., SHEN, Y. A., HAHN, A. T., MCGEE, A. W., XU, X., ZHENG, B., ZHANG, L. I., ROWITCH, D. H., FRANKLIN, R. J., LU, Q. R. & CHAN, J. R. 2012. Neurite outgrowth inhibitor Nogo-A establishes spatial segregation and extent of oligodendrocyte myelination. Proc Natl Acad Sci U S A, 109, 1299-304. CRISTE, G., TRAPP, B. & DUTTA, R. 2014. Axonal loss in multiple sclerosis: causes and mechanisms. Handb Clin Neurol, 122, 101-13. DE STEFANO, N., MATTHEWS, P. M., FU, L., NARAYANAN, S., STANLEY, J., FRANCIS, G. S., ANTEL, J. P. & ARNOLD, D. L. 1998. Axonal damage correlates with disability in patients with relapsing-remitting multiple sclerosis. Results of a longitudinal magnetic resonance spectroscopy study. Brain, 121 ( Pt 8), 1469-77. DEISENHAMMER, F., ZETTERBERG, H., FITZNER, B. & ZETTL, U. K. 2019. The Cerebrospinal Fluid in Multiple Sclerosis. Front Immunol, 10, 726. DOMENICONI, M., CAO, Z., SPENCER, T., SIVASANKARAN, R., WANG, K., NIKULINA, E., KIMURA, N., CAI, H., DENG, K., GAO, Y., HE, Z. & FILBIN, M. 2002. Myelin- associated glycoprotein interacts with the Nogo66 receptor to inhibit neurite outgrowth. Neuron, 35, 283-90. FLACHENECKER, P., KOBELT, G., BERG, J., CAPSA, D. & GANNEDAHL, M. 2017. New insights into the burden and costs of multiple sclerosis in Europe: Results for Germany. Mult Scler, 23, 78-90. FOURNIER, A. E., GRANDPRÉ, T., GOULD, G., WANG, X. & STRITTMATTER, S. M. 2002. Nogo and the Nogo-66 receptor. Prog Brain Res, 137, 361-9. FOURNIER, A. E., GRANDPRE, T. & STRITTMATTER, S. M. 2001. Identification of a receptor mediating Nogo-66 inhibition of axonal regeneration. Nature, 409, 341-6. FRIEDMAN, W. J. 2000. Neurotrophins induce death of hippocampal neurons via the p75 receptor. J Neurosci, 20, 6340-6. FRIEDMAN, W. J. & GREENE, L. A. 1999. Neurotrophin signaling via Trks and p75. Exp Cell Res, 253, 131-42. FRÜHBEIS, C., KUO-ELSNER, W. P., MÜLLER, C., BARTH, K., PERIS, L., TENZER, S., MÖBIUS, W., WERNER, H. B., NAVE, K. A., FRÖHLICH, D. & KRÄMER-ALBERS, E. M. 2020. Oligodendrocytes support axonal transport and maintenance via exosome secretion. PLoS Biol, 18, e3000621. FU, Q. L., HU, B., WU, W., PEPINSKY, R. B., MI, S. & SO, K. F. 2008. Blocking LINGO-1 function promotes retinal ganglion cell survival following ocular hypertension and optic nerve transection. Invest Ophthalmol Vis Sci, 49, 975-85. GALLO, G. & LETOURNEAU, P. C. 2004. Regulation of growth cone actin filaments by guidance cues. J Neurobiol, 58, 92-102. GENSERT, J. M. & GOLDMAN, J. E. 1997. Endogenous progenitors remyelinate demyelinated axons in the adult CNS. Neuron, 19, 197-203. GOLDSCHMIDT, T., ANTEL, J., KÖNIG, F. B., BRÜCK, W. & KUHLMANN, T. 2009. Remyelination capacity of the MS brain decreases with disease chronicity. Neurology, 72, 1914-21. GRUCHOT, J., WEYERS, V., GÖTTLE, P., FÖRSTER, M., HARTUNG, H. P., KÜRY, P. & KREMER, D. 2019. The Molecular Basis for Remyelination Failure in Multiple Sclerosis. Cells, 8. HAGEMEIER, K., BRUCK, W. & KUHLMANN, T. 2012. Multiple sclerosis - remyelination failure as a cause of disease progression. Histol Histopathol, 27, 277-87. HEMMER, B. & AL., E. 2021. Diagnose und Therapie der Multiplen Sklerose, Neuromyelitis- optica-Spektrum-Erkrankungen und MOG-IgG-assoziierten Erkrankungen, S2k- Leitlinie. Leitlinien für Diagnostik und Therapie in der Neurologie. HEMMER, B., CEPOK, S., NESSLER, S. & SOMMER, N. 2002. Pathogenesis of multiple sclerosis: an update on immunology. Current Opinion in Neurology, 15, 227-231. HOLSTIEGE, J., STEFFEN, A., GOFFRIER, B. & BÄTZING, J. 2017. Epidemiologie der Multiplen Sklerose – eine populationsbasierte deutschlandweite Studie. HUFSCHMIDT, A., LÜCKING, C. H., RAUER, S. & GLOCKER, F. X. 2017. Neurologie compact - Für Klinik und Praxis, Thieme. JI, B., LI, M., WU, W.-T., YICK, L.-W., LEE, X., SHAO, Z., WANG, J., SO, K.-F., MCCOY, J. M., BLAKE PEPINSKY, R., MI, S. & RELTON, J. K. 2006. LINGO-1 antagonist promotes functional recovery and axonal sprouting after spinal cord injury. Molecular and Cellular Neuroscience, 33, 311-320. KATOH, H., AOKI, J., ICHIKAWA, A. & NEGISHI, M. 1998. p160 RhoA-binding kinase ROKalpha induces neurite retraction. J Biol Chem, 273, 2489-92. KATOH, H., NEGISHI, M. & ICHIKAWA, A. 1996. Prostaglandin E Receptor EP3 Subtype Induces Neurite Retraction via Small GTPase Rho *. Journal of Biological Chemistry, 271, 29780-29784. KIM, J. S. 2020. Development of a high-throughput drug screening platform for oligodendrocyte myelination (for progressive multiple sclerosis). KIM, J. Y., SUN, Q., OGLESBEE, M. & YOON, S. O. 2003. The role of ErbB2 signaling in the onset of terminal differentiation of oligodendrocytes in vivo. J Neurosci, 23, 5561-71. KIPP, M., VAN DER STAR, B., VOGEL, D. Y., PUENTES, F., VAN DER VALK, P., BAKER, D. & AMOR, S. 2012. Experimental in vivo and in vitro models of multiple sclerosis: EAE and beyond. Mult Scler Relat Disord, 1, 15-28. KOBE, B. & KAJAVA, A. V. 2001. The leucine-rich repeat as a protein recognition motif. Curr Opin Struct Biol, 11, 725-32. KUHLMANN, T., MIRON, V., CUI, Q., WEGNER, C., ANTEL, J. & BRÜCK, W. 2008. Differentiation block of oligodendroglial progenitor cells as a cause for remyelination failure in chronic multiple sclerosis. Brain, 131, 1749-58. KUTZELNIGG, A. & LASSMANN, H. 2005. Cortical lesions and brain atrophy in MS. J Neurol Sci, 233, 55-9. LEE, X., SHAO, Z., SHENG, G., PEPINSKY, B. & MI, S. 2014. LINGO-1 regulates oligodendrocyte differentiation by inhibiting ErbB2 translocation and activation in lipid rafts. Mol Cell Neurosci, 60, 36-42. LEE, Y., MORRISON, B. M., LI, Y., LENGACHER, S., FARAH, M. H., HOFFMAN, P. N., LIU, Y., TSINGALIA, A., JIN, L., ZHANG, P. W., PELLERIN, L., MAGISTRETTI, P. J. & ROTHSTEIN, J. D. 2012. Oligodendroglia metabolically support axons and contribute to neurodegeneration. Nature, 487, 443-8. LIEPINSH, E., ILAG, L. L., OTTING, G. & IBÁÑEZ, C. F. 1997. NMR structure of the death domain of the p75 neurotrophin receptor. Embo j, 16, 4999-5005. LIU, B. P., FOURNIER, A., GRANDPRÉ, T. & STRITTMATTER, S. M. 2002. Myelin- associated glycoprotein as a functional ligand for the Nogo-66 receptor. Science, 297, 1190-3. LOWENTHAL, A., VANSANDE, M. & KARCHER, D. 1960. The differential diagnosis of neurological diseases by fractionating electrophoretically the CSF gamma-globulins. J Neurochem, 6, 51-6. LÜ, H. Z., WANG, Y. X., LI, Y., FU, S. L., HANG, Q. & LU, P. H. 2008. Proliferation and differentiation of oligodendrocyte progenitor cells induced from rat embryonic neural precursor cells followed by flow cytometry. Cytometry A, 73, 754-60. MATHEW, S. J., HAUBERT, D., KRONKE, M. & LEPTIN, M. 2009. Looking beyond death: a morphogenetic role for the TNF signalling pathway. J Cell Sci, 122, 1939-46. MERRILL, J. E. 2009. In Vitro and In Vivo Pharmacological Models to Assess Demyelination and Remyelination. Neuropsychopharmacology, 34, 55-73. MESTAS, J. & HUGHES, C. C. 2004. Of mice and not men: differences between mouse and human immunology. J Immunol, 172, 2731-8. MI, S., LEE, X., SHAO, Z., THILL, G., JI, B., RELTON, J., LEVESQUE, M., ALLAIRE, N., PERRIN, S., SANDS, B., CROWELL, T., CATE, R. L., MCCOY, J. M. & PEPINSKY, R. B. 2004. LINGO-1 is a component of the Nogo-66 receptor/p75 signaling complex. Nat Neurosci, 7, 221-8. MI, S., MILLER, R. H., LEE, X., SCOTT, M. L., SHULAG-MORSKAYA, S., SHAO, Z., CHANG, J., THILL, G., LEVESQUE, M., ZHANG, M., HESSION, C., SAH, D., TRAPP, B., HE, Z., JUNG, V., MCCOY, J. M. & PEPINSKY, R. B. 2005. LINGO-1 negatively regulates myelination by oligodendrocytes. Nat Neurosci, 8, 745-51. MI, S., MILLER, R. H., TANG, W., LEE, X., HU, B., WU, W., ZHANG, Y., SHIELDS, C. B., ZHANG, Y., MIKLASZ, S., SHEA, D., MASON, J., FRANKLIN, R. J., JI, B., SHAO, Z., CHÉDOTAL, A., BERNARD, F., ROULOIS, A., XU, J., JUNG, V. & PEPINSKY, B. 2009. Promotion of central nervous system remyelination by induced differentiation of oligodendrocyte precursor cells. Ann Neurol, 65, 304-15. MI, S., PEPINSKY, B., SHAO, Z., GARBER STARK, E. A., MIKLASZ, S. & GRAFF, C. 2019. Sp35 antibodies and uses thereof. MI, S., SANDROCK, A. & MILLER, R. H. 2008. LINGO-1 and its role in CNS repair. Int J Biochem Cell Biol, 40, 1971-8. MIX, E., MEYER-RIENECKER, H., HARTUNG, H. P. & ZETTL, U. K. 2010. Animal models of multiple sclerosis--potentials and limitations. Prog Neurobiol, 92, 386-404. MOSYAK, L., WOOD, A., DWYER, B., BUDDHA, M., JOHNSON, M., AULABAUGH, A., ZHONG, X., PRESMAN, E., BENARD, S., KELLEHER, K., WILHELM, J., STAHL, M. L., KRIZ, R., GAO, Y., CAO, Z., LING, H. P., PANGALOS, M. N., WALSH, F. S. & SOMERS, W. S. 2006. The structure of the Lingo-1 ectodomain, a module implicated in central nervous system repair inhibition. J Biol Chem, 281, 36378-90. MSIF 2020. Atlas of MS – 3rd Edition. MÜLLER, T. 2016. Remyelinisierung — nur geringer Erfolg mit Anti-LINGO-Antikörper. InFo Neurologie & Psychiatrie, 18, 65-65. PAINTLIA, A. S., PAINTLIA, M. K., KHAN, M., VOLLMER, T., SINGH, A. K. & SINGH, I. 2005. HMG-CoA reductase inhibitor augments survival and differentiation of oligodendrocyte progenitors in animal model of multiple sclerosis. Faseb j, 19, 1407-21. PAINTLIA, A. S., PAINTLIA, M. K., SINGH, A. K. & SINGH, I. 2008. Inhibition of rho family functions by lovastatin promotes myelin repair in ameliorating experimental autoimmune encephalomyelitis. Mol Pharmacol, 73, 1381-93. PARK, S. K., MILLER, R., KRANE, I. & VARTANIAN, T. 2001. The erbB2 gene is required for the development of terminally differentiated spinal cord oligodendrocytes. J Cell Biol, 154, 1245-58. PASCHKE, R. & VOIGT, K. 2010. Physiologie, Thieme Verlag. PATERSON , P. Y. 1960. TRANSFER OF ALLERGIC ENCEPHALOMYELITIS IN RATS BY MEANS OF LYMPH NODE CELLS. Journal of Experimental Medicine, 111, 119-136. PEDRAZA, C. E., TAYLOR, C., PEREIRA, A., SENG, M., THAM, C. S., IZRAEL, M. & WEBB, M. 2014. Induction of oligodendrocyte differentiation and in vitro myelination by inhibition of rho-associated kinase. ASN Neuro, 6. PEPINSKY, R. B., ARNDT, J. W., QUAN, C., GAO, Y., QUINTERO-MONZON, O., LEE, X. & MI, S. 2014. Structure of the LINGO-1-anti-LINGO-1 Li81 antibody complex provides insights into the biology of LINGO-1 and the mechanism of action of the antibody therapy. J Pharmacol Exp Ther, 350, 110-23. PRIVAT, A., JACQUE, C., BOURRE, J. M., DUPOUEY, P. & BAUMANN, N. 1979. Absence of the major dense line in myelin of the mutant mouse "shiverer". Neurosci Lett, 12, 107- 12. QUARLES, P. M. A. R. H. 1999. Basic Neurochemistry: Molecular, Cellular and Medical Aspects, Lippincott-Raven. RODRIGUEZ-TÉBAR, A. & BARDE, Y. A. 1988. Binding characteristics of brain-derived neurotrophic factor to its receptors on neurons from the chick embryo. J Neurosci, 8, 3337-42. RODRIGUEZ-TÉBAR, A., DECHANT, G. & BARDE, Y. A. 1990. Binding of brain-derived neurotrophic factor to the nerve growth factor receptor. Neuron, 4, 487-92. RUDICK, R. A., LEE, J. C., NAKAMURA, K. & FISHER, E. 2009. Gray matter atrophy correlates with MS disability progression measured with MSFC but not EDSS. J Neurol Sci, 282, 106-11. RUSSELL;, W. M. S. & BURCH, R. L. 1959. The Principles of Humane Experimental Technique. Medical Journal of Australia, 1, 500-500. SCALTRITI, M. & BASELGA, J. 2006. The epidermal growth factor receptor pathway: a model for targeted therapy. Clin Cancer Res, 12, 5268-72. SCHWAB, N., SCHNEIDER-HOHENDORF, T., HOYT, T., GROSS, C. C., MEUTH, S. G., KLOTZ, L., FOLEY, J. F. & WIENDL, H. 2018. Anti-JCV serology during natalizumab treatment: Review and meta-analysis of 17 independent patient cohorts analyzing anti- John Cunningham polyoma virus sero-conversion rates under natalizumab treatment and differences between technical and biological sero-converters. Mult Scler, 24, 563-573. SCOLDING, N., FRANKLIN, R., STEVENS, S., HELDIN, C. H., COMPSTON, A. & NEWCOMBE, J. 1998. Oligodendrocyte progenitors are present in the normal adult human CNS and in the lesions of multiple sclerosis. Brain, 121 ( Pt 12), 2221-8. SIMONS, M. & NAVE, K. A. 2015. Oligodendrocytes: Myelination and Axonal Support. Cold Spring Harb Perspect Biol, 8, a020479. SRIRAM, S. & STEINER, I. 2005. Experimental allergic encephalomyelitis: a misleading model of multiple sclerosis. Ann Neurol, 58, 939-45. STROMNES, I. M. & GOVERMAN, J. M. 2006a. Active induction of experimental allergic encephalomyelitis. Nat Protoc, 1, 1810-9. STROMNES, I. M. & GOVERMAN, J. M. 2006b. Passive induction of experimental allergic encephalomyelitis. Nature Protocols, 1, 1952-1960. THOMSON, C. E., MCCULLOCH, M., SORENSON, A., BARNETT, S. C., SEED, B. V., GRIFFITHS, I. R. & MCLAUGHLIN, M. 2008. Myelinated, synapsing cultures of murine spinal cord--validation as an in vitro model of the central nervous system. Eur J Neurosci, 28, 1518-35. VARTANIAN, T., GOODEARL, A., VIEHÖVER, A. & FISCHBACH, G. 1997. Axonal neuregulin signals cells of the oligodendrocyte lineage through activation of HER4 and Schwann cells through HER2 and HER3. J Cell Biol, 137, 211-20. WANG, K. C., KIM, J. A., SIVASANKARAN, R., SEGAL, R. & HE, Z. 2002a. P75 interacts with the Nogo receptor as a co-receptor for Nogo, MAG and OMgp. Nature, 420, 74-8. WANG, K. C., KOPRIVICA, V., KIM, J. A., SIVASANKARAN, R., GUO, Y., NEVE, R. L. & HE, Z. 2002b. Oligodendrocyte-myelin glycoprotein is a Nogo receptor ligand that inhibits neurite outgrowth. Nature, 417, 941-4. WINTER, M., BAKSMEIER, C., STECKEL, J., BARMAN, S., MALVIYA, M., HARRER- KUSTER, M., HARTUNG, H. P. & GOEBELS, N. 2016. Dose-dependent inhibition of demyelination and microglia activation by IVIG. Ann Clin Transl Neurol, 3, 828-843. YAMASHITA, T. & TOHYAMA, M. 2003. The p75 receptor acts as a displacement factor that releases Rho from Rho-GDI. Nat Neurosci, 6, 461-7. YAN, H. & CHAO, M. V. 1991. Disruption of cysteine-rich repeats of the p75 nerve growth factor receptor leads to loss of ligand binding. Journal of Biological Chemistry, 266, 12099-12104. YARDEN, Y. & SLIWKOWSKI, M. X. 2001. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol, 2, 127-37. | |||||||
| Lizenz: |  Dieses Werk ist lizenziert unter einer Creative Commons Namensnennung 4.0 International Lizenz | |||||||
| Fachbereich / Einrichtung: | Medizinische Fakultät | |||||||
| Dokument erstellt am: | 09.07.2025 | |||||||
| Dateien geändert am: | 09.07.2025 | |||||||
| Promotionsantrag am: | 17.10.2022 | |||||||
| Datum der Promotion: | 26.06.2025 |
