Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - TRAIN-ERS (Endoplasmic Reticulum Stress in Health and Disease)

Teaser

ContextThe endoplasmic reticulum (ER) properly folds and processes transmembrane and secreted proteins. However environmental and genetic factors can disrupt ER function which causes misfolded and unfolded proteins to accumulate in the ER lumen – this in known as ER stress...

Summary

Context
The endoplasmic reticulum (ER) properly folds and processes transmembrane and secreted proteins. However environmental and genetic factors can disrupt ER function which causes misfolded and unfolded proteins to accumulate in the ER lumen – this in known as ER stress. Cells respond to different types of stress by activating stress response pathways. The response to ER stress is called the Unfolded Protein Response (UPR) and it aims to minimise damage to the cell and promote survival, however if the damage is too great it can ultimately trigger cell death. ER stress is a key factor in the development of many diseases including cancer, neurodegenerative disorders, metabolic syndromes and inflammatory diseases. Therefore 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.

The problem/issue being addressed
There is a serious gap in our understanding of the molecular complexity of the ER stress response, how it determines cell fate, how it connects with other cellular processes and pathways, how it is regulated and, importantly, how it is deregulated in disease. This lack of knowledge and shortage of scientists with the skills to conduct and apply research in this area is hindering efforts to exploit the ER stress response for therapeutic/diagnostic purposes. TRAINERS is bringing 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.

Why it is important for society
This project aims 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 is providing high level training for young researchers ensuring they gain multidisciplinary and intersectoral research and training opportunities. The project is strengthening links between academic researchers and industry partners accelerating discoveries in new therapeutics and diagnostics. Public engagement activities are contributing towards attracting students towards careers in biomedical science, assuring Europe’s continued capacity to innovate.

Overall objectives
Research objectives
1) Understand the molecular and cellular response to ER stress
2) Understand how ER stress contributes to the development/treatment resistance of disease.
3) Develop new therapies and diagnostic markers based on the ER stress response

Training objectives
1) Produce young researchers with a high level of scientific expertise.
2) Produce professionals with a broad portfolio of transferable skills
3) Create an active ESR-network

Work performed

In the 1st reporting period we (1) set up a functional network and recruited ESRs (2) initiated research projects and training and (3) significantly progressed interdisciplinary and intersectoral research, training and networking within the consortium.
TRAINERS has 3 research workpackages:
WP4 aims to better understand the molecular mechanisms underlying the ER stress response. The first series of OMICs experiments have been completed raising significant hypotheses on IRE1 biology. Models to functionally monitor the role of the ER stress pathways in the occurrence of inflammatory signals and/or cell death have been established and preliminary evidence indicates that PERK and its interactors play roles at MAMs.
WP5 aims to identify the role that ER stress signalling play in paediatric cancers (ERS6), breast cancer (ERS7), Amyotrophic Lateral Sclerosis (ALS) (ERS8), and critical care diseases such as shock and sepsis (ERS9). Work has progressed on identifying novel, pathologically significant genes downstream of the UPR and the ESRs have all acquired expertise in their respective experimental models.
WP6 aims to develop novel ER stress-associated therapies and diagnostic/prognostic markers. It is applying novel approaches and strategies and significant progress in computational screening, biomarker identification and the establishment of models for testing compounds has been achieved to date.

Final results

WP4 has progressed beyond state of the art in terms of defining the network of genes and cellular impacted by IRE1, identifying novel RIDD auto-regulatory networks and understanding the role PERK plays in ER-PM tethering. This WP will produce robust data and novel hypothesis about the molecular mechanisms underlying the ER stress response.
WP5 has progressed in terms of suggesting drugs that may be effective in rhabdomyosarcoma, investigating the role of IRE1 in EMT in breast cancer, developing and testing an IRE1-XBP1 gene signature in brain tissue from ALS and AD patients and developing in vitro and in vivo models of traumatic/haemorrhagic shock. This work will continue to generate robust data and novel hypothesis about identification and targeting of UPR factors in the different disease models.
WP6 has moved beyond state of the art in terms of 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. This WP will continue to generate and test novel modulators of key proteins involved in the ER stress response and develop array technology for diagnostic/prognostic purposes.
Impact
One expected impact of TRAINERS is to enhance research- and innovation-related human resources and skills, to realise the potential of individuals and to provide new career perspectives. This is now being achieved through excellent training courses, innovative research projects and secondments. The young researchers are rapidly developing into innovation-oriented young scientists with key boundary-spanning capabilities. It is notable that initial impact has already been achieved in line with our original expectations in terms of
• Training in transferable skills
• The development of each ESRs research and technical skills
• Enhanced exposure of ESRs to diverse work and cultural environments via secondments
• Establishment of a highly networked group conducive to the development of ideas for exploration and exploitation.
• ESRs are monitored and supported by PCDPs, supervisory panels and the supervisory board.

Private sector partners provide training and expertise that is not covered by the academic partners, allowing ESRs to benefit while also serving as an example of good practice for structured doctoral programs that incorporate private sector input. TRAINERS is also building sustainable networking and research interactions between the partners, and many of these interactions will extend beyond the duration of the TRAINERS programme. TRAINERS partners have brought their experience of the innovative doctoral training within TRAINERS back to their own institutions where it is serving as template for other doctoral programs.
Overall the generation of well-trained ESRs, the research that they are producing and the improved links between academia and industry are beginning to sustainably contribute to strengthening European innovation capacity.

Website & more info

More info: http://www.train-ers.eu.