Verfügbarkeit: Muscle-secreted factors in spinal muscular atrophy

Muscle-secreted factors in spinal muscular atrophy: CTRP3 at the interface of muscle and neuron

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Bibliographische Detailangaben
1. Verfasser:	Rehorst, Wiebke Adele (VerfasserIn)
Format:	Abschlussarbeit Buch
Sprache:	English
Veröffentlicht:	Köln 2019
Schlagworte:	Hochschulschrift
Online-Zugang:	Inhaltsverzeichnis Inhaltsverzeichnis
Beschreibung:	Zusammenfassung in deutscher und englischer Sprache
Beschreibung:	XII, 160 Seiten, Seite CLXI-CLXIII Illustrationen 21 cm

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adam_text	TABLE OF CONTENT TABLE OF CONTENT ............................................................................................................ I LIST OF FIGURES ...............................................................................................................IV LIST OF TABLES .................................................................................................................. V ABBREVIATIONS ................................................................................................................ VI SUMMARY ............................................................................................................................. IX ZUSAMMENFASSUNG ........................................................................................................ XI 1. INTRODUCTION ......................................................................................................... 1 1.1 AUTOSOMAL RECESSIVE PROXIMAL SPINAL MUSCULAR ATROPHY ....................................... 1 1.1.1 CLINICAL PATHOLOGY AND CLASSIFICATION .................................................................... 1 1.1.2 GENETICS OF SMA - SMN1 AND SMN2 GENES ..................................................... 3 1.1.3 SMN PROTEIN AND FUNCTION .................................................................................... 5 1.1.4 DYSREGULATED CELLULAR PATHWAYS IN SMA ............................................................. 7 1.1.5 SMA MOUSE MODELS ............................................................................................ 8 1.2 SMA - A MULTISYSTEM DISORDER .............................................................................. 10 1.2.1 SKELETAL MUSCLE .................................................................................................. 11 1.2.2 OTHER CELL TYPES AND TISSUES .............................................................................. 11 1.3 THE NEUROMUSCULAR JUNCTION ................................................................................. 13 1.3.1 NMJ FORMATION AND MAINTENANCE ...................................................................... 14 1.3.2 SECRETED PRESYNAPTIC ORGANIZERS AND NEUROTROPHIC FACTORS ............................... 16 1.3.3 NEUROTROPHIC GROWTH FACTOR SIGNALLING ................................................................ 17 1.3.4 THE NMJ IN SMA ................................................................................................ 18 1.4 SKELETAL MUSCLE AS AN ENDOCRINE ORGAN ............................................................... 20 1.4.1 PROTEIN SECRETION PATHWAYS ............................................................................... 20 1.4.2 MUSCLE SECRETOME .............................................................................................. 21 1.4.3 C1 Q/TUMOR NECROSIS FACTOR-RELATED PROTEIN 3 ..................................................... 22 2. AIMS OF THE STUDY ............................................................................................. 24 3. RESULTS .................................................................................................................. 26 3.1 QUANTITATIVE SCREENING OF MUSCLE-SECRETED PROTEINS ........................................... 26 3.1.1 SMN REDUCTION BY HALF DOES NOT AFFECT MYOGENIC DIFFERENTIATION .................... 26 3.1.2 PULSED SILAC LABELLING AND CLICK CHEMISTRY FOR QUANTITATIVE SECRETOME ANALYSIS 27 3.2 CTRP3 EXPRESSION IN SMA-LIKE MUSCLE CELLS AND A SEVERE SMA MOUSE MODEL 36 3.2.1 ABERRANT GROWTH OF SIDE POPULATIONS IN MONOCLONAL STABLE C2C12 CELL LINES.. 36 3.2.2 SMN-DEPLETED C2C12 MUSCLE CELLS SECRETE REDUCED LEVELS OF CTRP3 ........ 38 3.2.3 CTRP3 LEVELS ARE REDUCED IN TIBIALIS ANTERIOR MUSCLES OF SMA MICE ........... 40 3.2.4 CTRP3 LEVELS ARE REDUCED IN BRAIN OF SMA MICE ............................................. 42 3.2.5 CTRP3 BLOOD PLASMA LEVELS ARE REDUCED IN SMA MICE .................................. 43 3.2.6 CTRP3 LEVELS ARE HIGHLY VARIABLE IN MURINE PRIMARY MUSCLE CELLS .................. 45 3.2.7 CTRP3 LEVELS DO NOT DIFFER BETWEEN PRIMARY WT AND SMA MOTOR NEURONS ...47 3.3 DOWNSTREAM PATHWAYS OF CTRP3 IN MOTOR NEURONS .............................................49 3.3.1 CTRP3-TREATMENT REGULATES GROWTH AND SURVIVAL PATHWAYS IN NSC34 CELLS ..49 3.3.2 DOSAGE OPTIMIZATION OF RECOMBINANT CTRP3 TREATMENT OF MOTOR NEURONS .... 54 3.3.3 CTRP3 STIMULATES ERK AND AKT PHOSPHORYLATION IN MOTOR NEURON-LIKE NSC34 CELLS .................................................................................................................... 55 3.3.4 CTRP3 STIMULATES ERK AND S6K PHOSPHORYLATION IN PRIMARY WT AND SMA MOTOR NEURONS ................................................................................................... 58 3.3.5 CTRP3 STIMULATES PROTEIN SYNTHESIS IN NSC34 CELLS ...................................... 60 3.3.6 CTRP3 INCREASES SMN AND PEX5 PROTEIN LEVELS IN NSC34 CELLS .................. 61 3.3.7 CTRP3 INCREASES SMN AND VEGF PROTEIN LEVELS IN PRIMARY WT AND SMA MOTOR NEURONS ............................................................................................................... 62 3.4 PHYSIOLOGICAL ROLE OF CTRP3 IN MOTOR NEURONS AND NEUROMUSCULAR JUNCTIONS ...67 3.4.1 CTRP3 PROMOTES AXONAL GROWTH OF PRIMARY MOTOR NEURONS ............................ 67 3.4.2 NEUROMUSCULAR CO-CULTURE IN MICROFLUIDIC CHAMBERS ....................................... 68 4. DISCUSSION ............................................................................................................. 72 4.1 DO SMA MUSCLE CELLS SECRETE DIFFERENT PROTEIN SETS? ......................................... 73 4.1.1 SMN DEPLETION IN MYOTUBES AFFECTS PROTEIN SECRETION ...................................... 73 4.1.2 CTRP3 - A NOVEL CANDIDATE FOR SMA RESEARCH ................................................ 76 4.1.3 CTRP3 LEVELS ARE REDUCED IN BLOOD PLASMA AND TISSUES OF SMA MICE ............ 78 4.2 DO SMA MUSCLE-SECRETED PROTEINS HAVE A FUNCTIONAL IMPACT ON MOTOR NEURONS? 81 4.2.1 CTRP3 REGULATES TRANSLATION IN NSC34 CELLS ................................................... 81 4.2.2 A NOVEL NEUROTROPHIC FACTOR - CTRP3 REGULATES THE PI3K/AKT/MTOR PATHWAY ............................................................................................................... 82 4.2.3 CTRP3 INCREASES THE PROTEIN SYNTHESIS RATE, AND SMN AND VEGF LEVELS IN MOTOR NEURONS .................................................................................................... 83 4.2.4 PEX5 IS REDUCED IN SMN-DEPLETED MYOBLASTS AND REGULATED BY CTRP3 IN NSC34 CELLS ....................................................................................................... 85 4.2.5 CTRP3 RESCUES AXONAL OUTGROWTH DEFECTS IN SMA MOTOR NEURONS ................ 86 4.3 AXONAL PROTEIN SYNTHESIS AT THE NEUROMUSCULAR JUNCTION ...................................... 87 5. CONCLUDING REMARKS AND DIRECTIONS FOR FUTURE WORK .............. 90 6. MATERIALS AND METHODS. 92 6.1 MATERIALS 92 6.1.1 LABORATORY EQUIPMENT ........................................................................................ 92 6.1.2 CHEMICALS .......................................................................................................... 94 6.1.3 REAGENTS ............................................................................................................. 95 6.1.4 KITS AND OTHER EQUIPMENT .................................................................................. 97 6.1.5 ENZYMES ............................................................................................................ 97 6.1.6 RECOMBINANT PROTEINS ...................................................................................... 98 6.1.7 PRIMARY ANTIBODIES AND STAINING REAGENTS ....................................................... 98 6.1.8 SECONDARY ANTIBODIES ....................................................................................... 99 6.1.9 PRIMERS .............................................................................................................. 100 6.1.10 SIRNAS .............................................................................................................. 101 6.1.11 LENTIVIRAL VECTORS CARRYING SHRNA .................................................................. 101 6.1.12 CELL LINES ........................................................................................................... 101 6.1.13 MOUSE STRAIN ..................................................................................................... 102 6.1.14 SOLUTIONS AND MEDIA ......................................................................................... 102 6.1.15 SOFTWARE PACKAGES AND INTERNET DATABASES ................................................... 104 6.2 METHODS .................................................................................................................... 105 6.2.1 WORKING WITH LABORATORY MICE .......................................................................... 105 6.2.2 CELL CULTURE WORK ............................................................................................... 106 6.2.3 NUCLEIC ACID METHODS ...................................................................................... 111 6.2.4 PROTEINBIOCHEMISTRY METHODS .......................................................................... 116 6.2.5 MICROFLUIDIC CHAMBER WORK ............................................................................... 125 6.2.6 IMMUNOFLUORESCENCE METHODS ........................................................................ 127 6.2.7 STATISTICAL ANALYSES ........................................................................................... 129 7. REFERENCES ............................ 130 8. PUBLICATIONS, PRESENTATIONS AND SCHOLARSHIPS ............................ 158 ACKNOWLEDGMENTS .................................................................................................. CLXI EIDESSTATTLICHE ERKLARUNG CLXIII
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author	Rehorst, Wiebke Adele
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spelling	Rehorst, Wiebke Adele Verfasser (DE-588)1188762672 aut Muscle-secreted factors in spinal muscular atrophy CTRP3 at the interface of muscle and neuron vorgelegt von Wiebke Adele Rehorst Köln 2019 XII, 160 Seiten, Seite CLXI-CLXIII Illustrationen 21 cm txt rdacontent n rdamedia nc rdacarrier Zusammenfassung in deutscher und englischer Sprache Dissertation Universität zu Köln 2019 (DE-588)4113937-9 Hochschulschrift gnd-content B:DE-101 application/pdf http://d-nb.info/1191381269/04 Inhaltsverzeichnis DNB Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=031638813&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis
spellingShingle	Rehorst, Wiebke Adele Muscle-secreted factors in spinal muscular atrophy CTRP3 at the interface of muscle and neuron
subject_GND	(DE-588)4113937-9
title	Muscle-secreted factors in spinal muscular atrophy CTRP3 at the interface of muscle and neuron
title_auth	Muscle-secreted factors in spinal muscular atrophy CTRP3 at the interface of muscle and neuron
title_exact_search	Muscle-secreted factors in spinal muscular atrophy CTRP3 at the interface of muscle and neuron
title_full	Muscle-secreted factors in spinal muscular atrophy CTRP3 at the interface of muscle and neuron vorgelegt von Wiebke Adele Rehorst
title_fullStr	Muscle-secreted factors in spinal muscular atrophy CTRP3 at the interface of muscle and neuron vorgelegt von Wiebke Adele Rehorst
title_full_unstemmed	Muscle-secreted factors in spinal muscular atrophy CTRP3 at the interface of muscle and neuron vorgelegt von Wiebke Adele Rehorst
title_short	Muscle-secreted factors in spinal muscular atrophy
title_sort	muscle secreted factors in spinal muscular atrophy ctrp3 at the interface of muscle and neuron
title_sub	CTRP3 at the interface of muscle and neuron
topic_facet	Hochschulschrift
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