Training network in drug discovery targeting TRIM Ubiquitin ligases in disease

Informations projet

TRIM-NET

N° de convention de subvention: 813599

DOI

10.3030/813599

Projet clôturé

Date de signature de la CE 30 Août 2018

Date de début 1 Janvier 2019

Date de fin 30 Juin 2023

Financé au titre de

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Coût total

€ 3 203 448,48

Contribution de l’UE

€ 3 203 448,48

Coordonné par

UNIVERSITA DEGLI STUDI DI TRIESTE
Italy

Periodic Reporting for period 2 - TRIM-NET (Training network in drug discovery targeting TRIM Ubiquitin ligases in disease)

Période du rapport: 2021-01-01 au 2023-06-30

Résumé du contexte et des objectifs généraux du projet

In all organisms, proteins need to be regulated throughout their life: when to be degraded and, possibly, substituted; where they need to be localised in the cell; and when they have to exert their function. A rapid way to ensure this regulation is by means of a modification called ubiquitination, a process through which proteins are flagged with a small protein called ubiquitin. This signature is read by other proteins that can interpret it either heading the tagged protein to programmed degradation or regulating its activity. Virtually all proteins in a cell can be modified through ubiquitination at defined moments of their life. Ubiquitination must therefore be tightly regulated and is controlled through a biochemical network that is necessary to attach ubiquitin to the specific target protein, either as a single entity or as a chain of several ubiquitins. The specificity of the ubiquitination process is guaranteed by E3 ubiquitin ligases, the enzymes that bring the substrate in close proximity to the ubiquitination machinery allowing the correct transfer of ubiquitin to the target protein. Ubiquitin tagging is a reversible process and deubiquitinating enzymes can erase this modification.

If the E3 ubiquitin ligases do not work properly, the consequences in the cells can be deleterious and indeed genetic and non-genetic alterations of these enzymes are associated with several pathological conditions.

The subject addressed by the TRIM-NET project was the study of a large family of E3 ubiquitin ligases, the Tripartite Motif (TRIM) proteins. Several TRIM proteins are implicated in common and rare human diseases and the goal of the project was the identification of disease mechanisms in which they are implicated to then be able to design therapeutic strategies. As TRIM proteins share a very similar domain structure, we established a scientific critical mass with complementary expertise bringing together a multidisciplinary international team that connects different competences on TRIM proteins: genetics, biochemistry, molecular and cell biology, chemical and structural biology.

The TRIM-NET research programme aimed at determining: i) how TRIM proteins contribute to disease and ii) how this information can help to develop therapeutic interventions. The parallel goal of the TRIM-NET consortium was to train young researchers in this area of biomedicine research preparing them for a future career in academia, industry or other science-related environments.

During the course of this project, we defined some of the pathological mechanisms involving TRIM E3 ubiquitin ligases in different diseases and some of these findings allowed the design and initial development of novel therapeutic strategies. These will be fully exploited to obtain possible drugs, thus heavily impacting on public health and eventually on society. The TRIM-NET outcomes will be also further developed scientifically as they are made available, through an open access mode, to the scientific community.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

To pursue the TRIM-NET goals, 12 highly motivated Early Stage Researchers (ESRs) were recruited and enrolled in doctoral programmes. ESRs carried out individual research projects dealing with the study of TRIM E3 ubiquitin ligases within the consortium towards the project’s goal. TRIM-NET research formed the basis of their training programme and was integrated with technical and transferrable skills courses, organised by the network, to provide them with multidisciplinary knowledge in biomedical research. These courses saw the active involvement of TRIM-NET public and private Partner Organisations, thus assuring inter-sectorial exposure and awareness.

TRIM-NET research contributed to a better understanding of the patho-physiological cellular mechanisms of several TRIM proteins in different pathologies: rare genetic diseases (e.g. TRIM-like malin in a form of epilepsy called Lafora disease; TRIM32 in a form of muscular dystrophy; TRIM18/MID1 in X-linked Opitz G/BBB Syndrome); neurodegenerative and muscular diseases (e.g. TRIM17 and TRIM41 in Parkinson’s disease; TRIM63/MuRF1 in chronic disease-linked muscle atrophy); and diverse types of cancers (TRIM25, TRIM24, TRIM28, and TRIM33 in prostate cancer; TRIM33 in breast cancer; TRIM8 in glioblastoma; and TRIM19/PML in Acute Promyelocytic Leukaemia).
These findings, together with chemical biology studies, allowed the design of novel therapeutic strategies to target some of the identified TRIM-target interactions and other druggable newly identified pathways. This led to the development of dedicated assays suitable for high-throughput screening and to screens to identify TRIM inhibitors/modulators. The TRIM-NET project allowed the identification of potential lead compounds for further exploitation.

Further, scientific articles have been published, while others are submitted for publications, reporting the results obtained. The results have been presented at meetings and also described in lay terms to the general public, including patients’ associations (cancers, dystrophy), during outreach events.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

Strengthening European innovation capacity - Given their critical role in different diseases, TRIM proteins represent excellent candidate targets for drug development. Intense interdisciplinary collaborative efforts between labs of the TRIM-NET consortium and through ESRs’ secondments, allowed to maximise the results and to set a stable ground also for continuous interactions. Also, from the intellectual point of view, the lively discussions at network-wide meetings and the concrete participation of private sector Partner Organisations, opened novel perspectives and boosted innovative capacity of the entire network at international level fostering also the future full exploitation of the findings.

Enhancing the career perspectives and employability of early stage researchers – Through exposure to state-of-the-art research environments, interdisciplinary research, and private sectors, TRIM-NET provided ESRs with the skills to realise their full potential as scientists in the field of biomedical research and drug discovery, whether it be in academia or outside. Finally, the consortium strongly believes that the positive attitude towards collaborative efforts will inspire others and that TRIM-NET will help to set the stage for further synergistic and collaborative research and foster both general and scientific interest in European research programmes.

Contribution to structuring doctoral/early stage research training at the European level – Research teams within and outside the TRIM-NET consortium appreciated the quality of the network’s activities and showed great interest in European funding programmes. Scientific exchanges between laboratories also made other researchers aware of the benefits of collaborative research programmes. Finally, interactions with local doctoral schools contributed to structuring doctoral and early stage research training at the European level by initiating collaborations and sharing practices.

Scheme of the TRIM-NET research project

TRIM-NET logo