TNKS inhibition counteract pro-fibrotic WNT/YAP signaling pathways activated by inflammatory cytokines, and consequently fibroblast-myofibroblast transition (FMT) and fibrogenesis/ extracellular matrix (ECM) deposition.
Work environment
The Cell Signaling and Drug Discovery research group is located at the Department of Immunology (IMM) at Oslo University Hospital – Rikshospitalet and is led by Group Leader Jo Waaler (www.ous-research.no/waaler). The group will consist of 2-3 postdocs and 2-3 technicians along with Master's students. The research group is also associated with the RCN Centre of Excellence (SFF) - Hybrid Technology Hub - Centre for Organ on a Chip-Technology: www.med.uio.no/hth/english. Jo Waaler has functioned as a supervisor for 13 Master’s students.
The research group focuses on tankyrase 1 and tankyrase 2 (TNKS1/2), enzymes from the PARP family that regulate protein activity, interactions, and degradation through mono- or poly-ADP-ribosylation and downstream cell signaling. TNKS1/2 proteins are key players in the regulation of WNT/β-catenin and Hippo signaling pathways, which are implicated in various diseases, including cancer, immune evasion and fibrosis. Consequently, significant efforts have been dedicated to developing selective TNKS1/2 inhibitors.
Oslo University Hospital has established itself as a leading center for chemical biology and has developed a small-molecule TNKS inhibitor program. These inhibitors modulate several target proteins, such as AXIN1 and AXIN2 in the β-catenin destruction complex, thereby inhibiting WNT/β-catenin signaling, and AMOT proteins in the Hippo signaling pathway, leading to YAP signaling inhibition.
Background
Interstitial lung disease (ILD) encompasses a range of conditions characterized by lung scarring or fibrosis, including idiopathic pulmonary fibrosis (IPF), which is particularly severe and often fatal. IPF, with a median survival of approximately three years post-diagnosis, currently lacks a cure. The existing treatments, Pirfenidone and Nintedanib, offer limited efficacy and are associated with significant side effects. This highlights a critical unmet medical need and underscores the importance of developing more effective therapeutic interventions to slow or potentially reverse disease progression. In this context, we have obtained preliminary data from cell culture, human patient material and animal models evaluating a novel anti-fibrotic treatment regimen involving the TNKS/WNT/YAP signaling inhibitor OM-153, a leading-edge compound developed at Oslo University Hospital. Notably, there are no existing therapeutic strategies targeting WNT/β-catenin and YAP signaling pathways for any disease, including lung fibrosis. Our research project aims to establish and evaluate advanced test systems for fibrosis research, incorporating multi-component cytokine stimuli to induce fibrogenesis, rather than relying solely on traditional single TGFβ stimuli. By employing these innovative models and state-of-the-art technologies in lung fibrosis research, we seek to enhance the understanding of the therapeutic effects and mechanisms of action of the TNKS inhibitor.
The alveolar epithelium consists of type 1 (AT1) cells, which arise from type 2 (AT2) progenitors. Following injury, AT2 cells proliferate and differentiate to restore the AT1 layer. In fibrosis, this differentiation is impaired, leading to accumulation of transitional AT2/AT1 cells with aberrant phenotypes, defective AT1 renewal, and failed epithelial repair.
Aims
For this research project, building on unpublished data focusing on human lung fibroblasts, we aim to expand the research efforts of TNKS inhibition in IPF treatment to other cells in the lung environment. In light of new evidence suggesting that lung epithelial cells are central drivers of injury responses and maladaptive remodeling in the development of IPF, we will establish lung epithelial cell cultures in our lab to test both the tolerability and therapeutic effects of TNKS inhibition in these systems. We also aim to analyze the effects of TNKS inhibition in rodent lungs and tissue samples.
- Evaluate how TNKS inhibition modulates WNT/β?catenin and YAP signaling in AT2/AT1?like epithelial cells.
- Determine the effects of TNKS inhibition on epithelial fate (AT2 maintenance, AT2→AT1 differentiation) and maladaptive states (senescence/partial EMT) and on epithelial barrier function.
- Assess epithelial–fibroblast cross?talk by testing how TNKS?modulated epithelial secretomes influence fibroblast activation and extracellular matrix deposition, and compare effects to standard?of?care agents (e.g., nintedanib).
- Establish and apply a rat precision?cut lung slice platform (from in vivo–harvested lungs) to evaluate pharmacodynamic responses to TNKS inhibition across epithelial and stromal markers ex vivo.
Possible methods and techniques
- Conduct experiments on 2D and 3D cell cultures.
- Carry out experiments using human and rat lung patient material.
- Isolation of lung cells and immune cell populations.
- Perform flow cytometry, immune cell phenotyping and scRNA sequencing.
- Conduct immunoassays/ELISA and multiplex ELISA.
- Basic laboratory and cell signaling pathway analysis techniques: i.e. treatment with small-molecule inhibitors and siRNA, CRISPR-Cas9 gene knockout, RT-qPCR, Western blot analysis and immunofluorescence/immunohistochemistry/ microscopy.
- Prepare samples and carry out transcriptomic analyses.
- Produce data for publication in scientific papers and present results at national conferences.
We offer
- Research Involvement: Participate in a versatile and ambitious research project.
- Work Environment: Engage in an international, challenging, stimulating, and attractive research setting.
- Career Development: Receive opportunities and support to advance your career.
- Technical Training: Gain hands-on experience with both basic and cutting-edge techniques in cancer/cell biology, molecular biology, and mouse animal models.
- Publication & Strategy: Collaborate with your supervisor to develop research strategies and receive proper credit for work aimed at publication in international peer-reviewed journals.
- Scientific Communication: Develop dissemination skills through training in oral presentations and scientific writing.
- Collaborative Learning: Participate in weekly lab meetings and journal clubs to share expertise and receive support in literature searches.
- Community & Social Events: Take part in regular social activities, including summer and Christmas parties, as well as group retreats.
What we expect from the Master’s student
- Commitment to the Project: Stay faithful to the project plan, adhere to ethical and institutional guidelines, and work with the supervisor to meet deadlines.
- Motivation & Initiative: Be highly motivated, proactive, and curious, with a strong interest in working in an internationally competitive laboratory.
- Time Management: Be a full-time student who takes responsibility for planning and managing your own time effectively.
- Literature & Understanding: Read relevant literature and dedicate significant time to fully understand the project.
- Independence & Collaboration: Aim to become an independent laboratory worker after the training period (1–2 months) while recognizing when to seek help.
- Presentation Skills: Present your work in internal/external meetings to develop communication skills and prepare for your final examination.
Contact Persons
Main supervisor:
External at Rikshospitalet: Jo Waaler, PhD (Group leader), jo.waaler@medisin.uio.no
Internal at IBV: Fahri Saatcioglu or Roger Sim
Co-supervisors:
Karl Martin Forbord, PhD (PostDoc), k.m.f.forbord@medisin.uio.no
Maria Candamo-Lourido (Technician), maria.candamo-lourido@medisin.uio.no