ERC-Starting Grant-”tRNAtoGO” project - 1,5 million € (2020-2024)
Cells integrate internal and external stimuli by continuously adapting their transcription and translation. tRNAs are heterogeneous and highly modified molecules necessary to correctly translate mRNAs into proteins. Although their discovery dates back to the end of the 1950s, it is only in recent years that their active role in regulating translation has begun to be highlighted, both in the field of health and disease. Cancer stem cells (CSCs) are a small population of transformed cells capable of supporting tumour growth and responsible for metastasis and drug resistance.
The incredible plasticity and genetic heterogeneity of CSCs make it extremely difficult to find global markers and/or molecular fingerprints expressed only by these cells. The tRNAtoGO project, led by Francesca Rapino, F.R.S.-FNRS Research Associate at the Cells-Cancer Signaling laboratory (GIGA Stem Cells), postulates that the expression of a specific signature of tRNA molecules allows the establishment of onco-proteomes supporting the transformation of cancer stem cells.
Francesca Rapino wants to understand the silent conditions (tRNA) that "prime" a population of healthy cells to become tumorigenic. Advanced technologies will be used to profile, genetically screen and physiologically test the role of different tRNAs in the establishment of CSC. By identifying a signature of the tRNAs that characterize the establishment of CSC, the researcher hopes to generate in the near future a new technology to improve the early diagnosis of highly incurable cancers such as lung and intestinal cancer.
ERC-Starting Grant-projet ”IM-ID” - 1,5 million € (2019-2023)
The mechanisms underlying lung homeostasis are of fundamental biological importance and have critical implications for the prevention of immune-mediated diseases such as asthma. The Laboratory of Cellular and Molecular Immunology has previously demonstrated that lung Interstitial Macrophages (IM) exhibit a tolerogenic profile and are able to prevent and limit the development of aberrant immune responses against allergens (such as seen in asthma), thus underscoring their role as crucial regulators of lung homeostasis. In addition, the laboratory has shown that IM could expand from monocyte precursors upon host exposure to bacterial unmethylated CpG-DNA, resulting in robust protection against allergic asthma. To date, however, IM have only been characterized as a bulk population in functional studies, and little is known about the tissue-instructive signals, specific transcription factors and differentiation programs which contribute to determining their identity (ID) and function. In this project, Thomas and his team will define the precise ID of IM (i.e. their spatial organization, heterogeneity, molecular signature and the specific TF governing their differentiation and function), and investigate how IM ID is imprinted by the local niche to sustain lung homeostasis. This research will increase the understanding of the basic mechanisms underlying the fine-tuning of tolerogenic IM and will thus provide robust foundations for novel IM-targeted approaches promoting health and preventing airway diseases in which IM (dys)functions have been implicated.
ERC-Starting Grant - Projet ”COGNAP” - 1,5 million € (2018-2023)
All of us know of individuals who remain cognitively sharp at an advanced age. Identifying novel factors which associate with inter-individual variability in -and can be considered protective for- cognitive decline is a promising area in ageing research. Considering its strong implication in neuroprotective function, COGNAP predicts that variability in circadian rhythmicity explains a significant part of the age-related changes in human cognition. Circadian rhythms -one of the most fundamental processes of living organisms- are present throughout the nervous system and act on cognitive brain function. Circadian rhythms shape the temporal organizationof sleep and wakefulness to achieve human diurnality, characterized by a consolidated bout of sleep during night-time and a continuous period of wakefulness during the day. Of prime importance is that the temporal organization of sleep and wakefulness evolves throughout the adult lifespan, leading to higher sleepwake fragmentation with ageing. The increasing occurrence of daytime napping is the most visible manifestation of this fragmentation. Contrary to the common belief, napping stands as a health risk factor in seniorsin epidemiological data. I posit that chronic napping in older people primarily reflects circadian disruption. Based on my preliminary findings, I predict that this disruption will lead to lower cognitive fitness. I further hypothesise that a re-stabilization ofcircadian sleep-wake organization through a nap prevention intervention will reduce age-related cognitive decline. Characterizing thelink between cognitive ageing and the temporal distribution of sleep and wakefulness will not only bring ground-breaking advancesatthe scientific level, but is also timely in the ageing society. Cognitive decline, as well as inadequately timed sleep, represent dominant determinants of the health span of our fast ageing population and easy implementable intervention programs are urgently needed.
ERC-Consolidator Grant - Projet ”INSITE” - 2 Million € (2018-2013)
Tissue Engineering (TE) refers to the branch of medicine that aims to replace or regenerate functional tissue or organs using man-made living implants. As the field is moving towards more complex TE constructs with sophisticated functionalities, there is a lack of dedicated in vitro devices that allow testing the response of the complex construct as a whole, prior to implantation. Additionally, the knowledge accumulated from mechanistic and empirical in vitro and in vivo studies is often underused in the development of novel constructs due to a lack of integration of all the data in a single, in silico, platform. The INSITE project aims to address both challenges by developing a new mesofluidics set-up for in vitro testing of TE constructs and by developing dedicated multiscale and multiphysics models that aggregate the available data and use these to design complex constructs and proper mesofluidics settings for in vitro testing. The combination of these in silico and in vitro approaches will lead to an integrated knowledge-rich mesofluidics system that provides an in vivo-like time-varying in vitro environment. The system will emulate the in vivo environment present at the (early) stages of bone regeneration including the vascularization process and the innate immune response. A proof of concept will be delivered for complex TE constructs for large bone defects and infected fractures. To realize this project, Liesbet Geris can draw on her well-published track record and extensive network in the fields of in silico medicine and skeletal TE. If successful, INSITE will generate a shift from in vivo to in vitro work and hence a transformation of the classical R&D pipeline. Using this system will allow for a maximum of relevant in vitro research prior to the in vivo phase, which is highly needed in academia and industry with the increasing ethical (3R), financial and regulatory constraints.
ERC-Consolidator Grant - Projet ”PV-COAT” - 2 Million € (2015-2020)
Heart valve prostheses are currently among the most widely used cardiovascular devices. To maintain enduring optimal biomechanical properties, the mechanical prostheses, based on carbon, metallic and polymeric components, require permanent anticoagulation, which often leads to adverse reactions, i.e. higher risks of thromboembolism, hemorrhage, and hemolysis. Continuing advances in heart valve prosthesis design and in techniques for implantation have improved the survival length and quality of life of patients who receive these devices. In an ongoing effort to develop a more durable and biocompatible heart valve prosthesis, researchers have used a variety of techniques to determine the suitability of given valve materials for a given implant application. In recent years, advances in polymer science have given rise to new ways of improving artificial cardiovascular devices biostability and hemocompatibility. To date, no polymer coated mechanical prosthetic heart valve exists. The present research project aims to improve the hemocompatibility and long-term in vivo performance of mechanical prosthetic heart valves by reducing contact-induced thrombosis through bioactive polymer prosthetic valve surface coating. These new coated prosthetic heart valves will be designed for hemodynamic performance and durability similar to uncoated materials, combined with a greater thromboresistance, both in vitro and in animal studies. With these promising advances, bioactive surface coated prosthetic heart valves could replace previous generation of prosthetic valves in the near future. The utmost perspective of the current project paves the way for the development of new bioactive coating for other implantable cardiovascular devices or materials.