Running Project ERIBA
REGENERATE-IT
Grant: HORIZON-TMA-MSCA-DN
Research Field: Stem cell biology, Tissue engineering, Gene therapy, cell therapy, regenerative medicine
Prinicpal Investigator: Eugene Berezikov
The REGENERATE-IT Network brings together a full spectrum of disciplines – from fundamental to applied research – to train the next generation of researchers in regenerative biology and adjacent fields. While the natural regenerative ability of humans is limited, some animals have remarkable regenerative capacity. For example, planarian flatworms can restore all body parts from small pieces of tissue, salamanders can grow back lost limbs and repair damaged eyes, and zebrafish can regenerate their heart and fins. By
identifying the common biological principles underlying the regenerative processes in these different animal models, we can learn a great deal on how to improve regenerative interventions in humans. Currently, regenerative animal models are studied in isolation, preventing the discovery of such shared mechanisms, and the REGENERATE-IT Network fills this gap. ESRs trained by REGENERATE-IT will obtain a broad and unique understanding of the fundamentals of regenerative biology and of the needs of research in
regenerative medicine. The REGENERATE-IT Network therefore includes scientists working on regenerative model organisms such as flatworms, cnidarians, crustaceans, amphibians and zebrafish; stem cell scientists working on mouse and human models; scientists with impressive track records in translational research and experience with clinical trials; and experts in key technologies such as genomics, single cell sequencing, imaging and drug screening. REGENERATE-IT will train 10 ESRs and 1 associated doctoral researcher through research, secondments to other laboratories, consortium meetings, and workshops covering a wide range of topics. In
addition to consolidating European strengths in regenerative biology, and training a cohort of next-generation scientists capable of
cross-disciplinary research, REGENERATE-IT will combine and deliver theoretical and technological breakthroughs, and advance the
frontiers of regenerative biology and medicine.
Understanding how cellular senescence contributes to the sexual dimorphism of hepatocellular carcinomas
Grant: KWF Research Project
Research Field: Cancer Progression and Metastasis, Liver Cancer
Principal Investigator: Marco Demaria
Human hepatocellular carcinoma (HCC) accounts for over 80% of primary liver cancers and ranks fourth in cancer-related mortality. The median survival post-diagnosis is 6 to 20 months, with a 5-year survival rate of only 10%. HCC is most prevalent in East Asia and Africa, but its incidence is rising in the US and Europe. Risk factors include hepatotoxic chemicals, alcohol/tobacco abuse, and chronic hepatitis B/C infections. Older individuals and men are at higher risk, with men having a significantly higher incidence (~4:1) than women. This sex disparity has been validated in mouse models, where HCC develops spontaneously in aging males but not females, suggesting intrinsic differences rather than lifestyle factors.
The immune system’s activity and composition are sex-biased, with females showing higher immune reactivity. This is due to higher numbers of macrophages, neutrophils, and CD4+ T cells, and a greater proportion of activated CD4+ and CD8+ T cells. Sex hormones play a crucial role, with estrogens enhancing immune responses and androgens suppressing them. Additionally, cellular senescence, a state of stable growth arrest, is influenced by sex hormones. Senescent cells, which accumulate with age and stress, can promote tumorigenesis through the Senescence-Associated Secretory Phenotype (SASP).
Our research suggests that senescent cells accumulate more in male livers, potentially contributing to higher HCC rates. We aim to demonstrate how senescent cells promote liver cancer and the mechanisms behind sex-dependent differences in senescence. Our objectives are to evaluate the sex-dependent accumulation and pro-tumorigenic effects of senescent cells in the liver and to understand the mechanisms regulating these differences. This research could lead to novel therapeutic approaches for HCC prevention and treatment by targeting senescence-associated mechanisms.
Rebalancing neurotransmission in ALS by targeting ion channels
Grant: ALS Foundation, ChannALS
Research Field: Neurodegenerative diseases, Molecular Neurobiology
Principal Investigator: Ellen Nollen
In this project, we propose to use the versatile model organism C. elegans to study ALS. This tiny, short-lived nematode has been used as a powerful tool in biomedical investigations and led to the discovery of disease mechanisms and drug targets. We and others have successfully used C. elegans for studying neurodegenerative diseases including Alzheimer’s. Parkinson’s and Huntington’s disease. As a model organism for ALS, C. elegans has several advantages, including its remarkable genetic and cellular similarity to humans, its short three-week lifespan which mirrors features of human aging, its fully mapped nervous system of just 302 cells that closely resembles that of humans, and its suitability for efficient, unbiased, and cost-effective behavioral genetic screens that require no ethical permissions.
In summary, our comprehensive project leverages the genetic and cellular similarity of C. elegans to humans to reveal potential therapeutic targets for suppression TDP-43-related motor impairment. Our approach is unique since we can study the involvement of ion-channels in motor impairment at the cellular, circuit and organismal level in a fast and systematic manner and focus on the consequences for movement. By first focusing on a detailed understanding of the properties of SLO-1 in this project, for which we know inhibition protects against motor impairment, we expect to provide mechanistic insights into potassium channels as prospective therapeutic targets for ALS. In addition, our collaboration with clinicians and researchers using human data will directly connect our findings to human studies, enhancing the potential of the project to contribute significantly to the development of treatments for ALS patients.
Holey trap – disordered proteins guard the gap
Grant: NWO Open Competition Domain Science – XL
Research Field: Nuclear pore complex, Molecular cell biology
Principal Investigator: Liesbeth Veenhoff
The selective control of import and export across membrane-spanning pores is vital for our cells. Typically, the specificity, speed, and directionality of transport are tightly woven into the ordered structure of the pore which is characterized by a limited conformational flexibility. Remarkably, nature also offers a fascinating and unexpected alternative strategy: by lining membrane pores with intrinsically disordered proteins (IDPs) to guard the gap. The best
example is the nuclear pore complex (NPC), responsible for all molecular transport in and out of the cell nucleus. These pores exhibit an intriguing selectivity where most proteins are blocked from transport, while particular transport receptor (TR) proteins, can pass to traverse their cargo. A mechanistic understanding of this puzzling selectivity has remained lacking.
The recent discovery of IDP-based pores in peroxisomes that are similarly selective but with a drastically reduced complexity, promises to now uncover – for the first time – general principles of IDP-based transport selectivity.
The aim of this proposal is to resolve the fundamentals of this IDP-mediated selective barrier function. We have composed a research team with an unrivalled combination of complementary expertise, comprising in-silico, in-vitro, in-vivo, and in-situ techniques, supplemented by world-leading experts in NPCs and peroxisomes. This uniquely allows to tackle the problem from opposite angles: (1) a wild type track that studies a selection of relevant biological systems with their full biological complexity (IDP-TR combinations, peroxisomes, nuclear pore complexes), and (2) a designer track in which we design the amino-acid sequence of the IDPs and TRs de novo from the bottom up and study these in biomimetic solid-state nanopores and reconstituted designer pores in yeast. This team and approach can be expected
to uncover the vital mechanism of selective IDP-mediated transport and thus answer one of the central questions in molecular cell biology.
How do chromosomal unstable tumours escape immune surveillance?
Grant: NWO VICI
Research Field: Cancer, Immune system, chromosomal instability
Principal Investigator: Floris Foijer
Cancer cells often make mistakes in dividing their chromosomes. Our previous work shows that these errors in healthy cells activate the immune system, but cancer cells bypass this. We will investigate exactly how cancer cells do this to find ways to get the immune system to clean up these messy cancer cells
