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Endoplasmic Reticulum Stress in Health and Disease

Periodic Reporting for period 2 - TRAIN-ERS (Endoplasmic Reticulum Stress in Health and Disease)

Reporting period: 2017-10-01 to 2019-09-30

The endoplasmic reticulum (ER) folds and processes transmembrane and secreted proteins. Environmental and genetic factors can disrupt ER function causing misfolded & unfolded proteins to accumulate in the ER lumen – known as ER stress. Cells respond to different stressors by activating response pathways. The response to ER stress is called the Unfolded Protein Response (UPR). It aims to minimise cell damage and promote survival. If the damage is too great it can trigger cell death. ER stress is a key factor in the development of many diseases including cancer, neurodegenerative disorders, metabolic syndromes and inflammatory diseases. The molecular and cellular response to ER stress represents a potential therapeutic intervention point for the development of new therapies and diagnostic/prognostic markers for many diseases.

There is a gap in our understanding of the molecular complexity of the ER stress response, how it determines cell fate, connects with other cellular processes and pathways, its regulation and, how it is deregulated in disease. This, coupled with limited numbers of skilled scientists in this area is hindering efforts to exploit the ER stress response for therapeutic/diagnostic purposes. TRAINERS brought young researchers together with world-leading academics, clinicians and industry personnel to increase understanding of the ER stress response and apply this understanding for the treatment of ER stress-associated diseases.

The main aim was to increase understanding of a fundamental biological process involved in the development of many common diseases and to apply this understanding to develop new therapies. This requires well trained researchers with a broad range of transferable skills. TRAINERS provided high level training for young researchers ensuring they gained multidisciplinary and intersectoral research and training opportunities. The project strengthened links between academic researchers and industry partners accelerating discoveries in new therapeutics and diagnostics. Public engagement activities contributed towards attracting students towards careers in biomedical science, assuring Europe’s continued capacity to innovate.

Outputs (presentations & publications) are already having an impact on the reputation of Europe for innovative and excellent research. Overall the generation of well-trained ESRs, the research produced and improved links between academia and industry have contributed to strengthening European innovation capacity and providing skilled researchers.
WP4 focused on the molecular mechanisms underlying the ER stress response. The OMICs experiments completed raised significant hypotheses on IRE1 biology. Models to monitor the role of the ER stress pathways in the occurrence of inflammatory signals and/or cell death were established and preliminary evidence indicated that PERK and its interactors play roles at MAMs. The work carried out has expanded our knowledge of ER stress signalling and UPR biology, identified strategies targeting components of the UPR in the context of different diseases and developed biomarkers that could help identify individual patients that could benefit the most from these solutions.

WP5 focused on identifying the role of ER stress signalling in paediatric cancers (ERS6), breast cancer (ERS7), ALS (ERS8), and critical care diseases (e.g. shock & sepsis) (ERS9). Work progressed on identifying novel, pathologically significant genes downstream of the UPR and all ESRs acquired expertise in experimental models. Activation of the UPR is recognised as a factor in several diseases including select cancers, neurodegenerative diseases, and traumatic haemorrhagic shock injury. We have validated IRE1 and PERK as useful therapeutic targets in models of cancer and neurodegenerative diseases. A suite of assays for the detection of IRE1 and PERK activity in biological samples including patient samples and model cell lines has been developed, and in cell-free systems for the study of potential drugs to target them.

WP6 goal was to develop novel ER stress-associated therapies and diagnostic/prognostic markers. It applied novel approaches and strategies to progress computational modeling for drug design, biomarker identification and established assay platforms for testing novel compounds with potential to modulate UPR. Both selective and dual targeting (PERK and IRE1) kinase inhibitors have been identified. In the case of IRE1 inhibitors, the optimized compounds clearly show an impact on XBP1 splicing. Patent filing and relevant commercial activities have been initiated. First steps towards preclinical testing are under way. A biochip measuring XBP1s and XBP1u is being developed into a final commercial product, a valuable tool in diagnosis as well as in monitoring response to treatment. Cytokine IL-8 has been identified as a potential biomarker for AML, and for malignant melanoma. The relation between high levels of unsaturated fatty acids and sensitivity towards ferroptosis has been established along with identification of Apolipoprotein E as a possible druggable target in order to sensitise M and T cell types to lipid peroxidation. The work accomplished has provided several new IP, drug candidates and products, and enabled new research relating to UPR mechanism and ER-stress as a therapeutic tool.
All research WPs progressed beyond state of the art, produced robust data and novel hypotheses. WP4 defined the network of genes and cellular impacted by IRE1, identified novel RIDD auto-regulatory networks and the role PERK plays in ER-PM tethering. WP5 identified drugs that may be effective in rhabdomyosarcoma, investigated the role of IRE1 in EMT in breast cancer, developed and tested an IRE1-XBP1 gene signature in brain tissue from ALS and AD patients and developed in vitro and in vivo models of traumatic/haemorrhagic shock. WP6 undertook virtual screening and testing of novel IRE1 and PERK inhibitors, establishing a translational model of glioblastoma from patient derived primary cells, identifying potential biomarkers for inclusion in a Biochip array and developing novel strategies to target therapy resistant melanoma. It generated and tested novel modulators of key proteins involved in the ER stress response and developed array technology for diagnostic/prognostic purposes.

One expected impact was enhanced research- and innovation-related human resources and skills. This was achieved through excellent training courses, innovative research projects and secondments. ESRs have developed into innovation-oriented young scientists with key boundary-spanning capabilities.TRAIN-ERS provided a unique structured training programme that benefited ESRs and provides a template for specialized structured training programmes. The combination of private sector involvement, opportunity for international and inter-sectoral secondments and complementary skills training offered by TRAINERS is unique and has had an impact on the traditional model of PhD training at partner institutions. TRAINERS is serving as a model long-term organisational and collaborative structure needed for sustainable multi-national training in academia and industry. Overall the generation of well-trained ESRs, the research that they produced and the improved links between academia and industry are sustainably contributing to strengthening European innovation capacity.
Canonical PERK kinase inhibitor binding mode
High IRE1 activity is associated with the aggressive basal breast cancer sub-type