Identification of novel compounds for Wnt/beta-catenin induced lung repair in COPD

Staschewski, Astrid (2021): Identification of novel compounds for Wnt/beta-catenin induced lung repair in COPD. Dissertation, LMU München: Medizinische Fakultät

Abstract

Regeneration and wound repair is a fascinating field with the question whether it can be induced pharmacologically by modulating developmental pathways like the Wnt/ß catenin pathway that is responsible for cell fate and tissue differentiation. One exemplifying disease model for chronic injury and wounding addressed in this thesis is COPD, chronic obstructive pulmonary disease. It is currently considered to be the 4th leading cause of death worldwide and there is no curable treatment available. COPD is mainly caused by cigarette smoking and is characterized by emphysema and chronic bronchitis which worsens progressively over time, destroying more and more lung tissue. As it had been previously observed that a GSK3 Inhibitor and Wnt/ß catenin activator, Lithium Chloride, could attenuate emphysema (Kneidinger et al., 2011; Uhl et al., 2015), the next step was to find other compounds that could likewise activate Wnt/ß catenin. Thus, we hypothesized that Wnt/ß catenin is a crucial regulator for inducing regeneration in emphysema. To conquer this problem, a high-throughput screen of 30.000 unique compounds had been previously conducted to identify potential new Wnt/ß catenin inducing compounds based on a TCF/LEF luciferase reporter assay in stably transfected 3T3 cells. Combined with the HitPick software as an in silico method to determine possible targets associated with Wnt signaling, a list of 5 FDA approved drugs was generated for further examination and secondary assays. As a first approach and thus the main objective of this thesis, the 5 FDA drugs were validated as Wnt/ß catenin activators and we examined in vitro drug toxicity and their ability to induce wound closure. Active Beta Catenin Protein expression was also investigated as well as further literature research to better understand the potential mechanisms of the drugs and their therapeutic potential. Focusing on FDA drugs could enable a faster translation into the clinic and clinical trials. Though having the great advantage of modern technology and robots making screenings possible in a high throughput manner, drug development and discovery for Wnt/ß catenin modulating drugs remains a challenge that will be later illuminated and discussed.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Keywords: COPD; Regeneration; Wound repair;Wnt Signalling; Wnt beta catenin pathway
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften ; 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Fakultäten: Medizinische Fakultät
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 19. Mai 2021
• 1. Bericht­erstatter:in: Königshoff, Melanie