ERC FUNDED PROJECTS

"Cytokine receptor signaling is an essential part of the intercellular communication networks that govern key physiological processes in the body. Cytokine dysfunction is associated with numerous pathologies including autoimmune disorders and cancer, and both cytokines and cytokine antagonists have found their way into the clinic. Yet, there are still many unfulfilled promises and opportunities. In this project we will reinvestigate key aspects of cytokine receptor activation and signaling using novel insights and techniques recently developed in our laboratory. This will include the AcTakine concept for cell-specific targeting of cytokine activity, and applications of our MAPPIT, KISS and Virotrap toolboxes to systematically map protein interactions involved in cytokine signaling. We expect to obtain important new insights, both in fundamental and in applied medical sciences."

2 487 728 €

Start date: 2014-02-01, End date: 2019-01-31

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of the motor neurons. As for other neurodegenerative disorders, translation of newly acquired biological insights into therapies has been difficult. In the current project we intend to contribute to the development of therapeutic approaches for ALS. We want to generate novel models, identify new therapeutic targets for intervention, and translate these into validated options for drug development in ALS. This will be done by establishing a continuous line of research from the (unbiased) screening for targets in a small animal model (zebrafish), to the exploration of their therapeutic potential, and the validation in patients. In addition, by exploring the significance of some of the findings for other neurodegenerative disorders, we hope to demonstrate this approach to be valid for the field of neurodegenerative disorders in general. This research will be performed bases on 6 work packages (WP): 1.screening of a zebrafish model for ALS to identify therapeutic targets; 2. validation of these targets in larger vertebrate ALS models; 3. investigation of the mechanism of action of these targets in order to establish approaches to interfere with them; 4. validation of these targets in human ALS; 5. generation of preclinical data on these targets; 6. exploration of the possible role of these targets in other neurodegenerative diseases. Results from WP1 will be used for further research in WP2, results from WP2 in WP3, etc. We have gathered a large set of data in preparatory work in zebrafish, enabling us to start all WPs from the beginning of the project on. This project involves collaborations with several other groups, national and international, which all have been established. Furthermore, all transgenic mice needed to initiate all these WPs have been generated and available to us.

2 467 990 €

Start date: 2014-05-01, End date: 2019-04-30

Humanity has always been intrigued by the nearly mythical properties of the brain. With its billions of neurons and innumerable connections, the brain is of such complex nature, that trying to understand it may seem a vain project. Yet, by using the ‘mini-brain’ of the model organism Caenorhabditis elegans, which shares many components with the human brain but counts only 302 neurons, thorough research can penetrate into this complexity. We here pursue to deliver a much-needed understanding of how learning and memory processes are regulated by neuropeptide signaling in the brain. Neuropeptides are small regulatory proteins that are implicated in a variety of processes. Growing evidence exists for their involvement in learning and memory, but how they exert these effects is largely unexplored. In C. elegans we recently disentangled a conserved vasopressin/ocytocin-related system that –as in humans– mediates associative learning. As such, we can deliver the experience, model and logical approach to provide detailed insights in neuropeptidergic control of learning and memory. We will first identify the endogenous ligand of all orphan C. elegans neuropeptide GPCRs, as this will provide the essential basis to build this project on. Mutants of neuropeptide-receptor pairs will then be tested for their ability to learn or maintain associative short- or long-term memory. We will also define in which cells and circuits relevant neuropeptides and receptors are needed for these functions, in order to generate models of neuropeptidergic control of learning and memory. We envisage the use of novel tools and cutting-edge experimental setups to take this research beyond its current horizon. Via single cell RNA sequencing, optogenetic analyses and in vivo calcium imaging, we will develop a workflow to build integrative models of associative learning and memory processes mediated by neuropeptides, which will serve as a scaffold for the study of these processes in more complex brains.

2 463 028 €

Start date: 2014-02-01, End date: 2019-01-31

RADICAL explores the idea that consciousness is something that the brain learns to do rather than a static property of certain neural states vs. others. Here, considering that consciousness is extended both in space and in time, I adopt a resolutely dynamical perspective that mandates an experimental approach focused on change, at different time scales. I suggest that consciousness arises as a result of the brain's continuous attempts at predicting not only the consequences of its actions on the world and on other agents, but also the consequences of activity in one cerebral region on activity in other regions. By this account, the brain continuously and unconsciously learns to redescribe its own activity to itself, so developing systems of metarepresentations that characterise and qualify the target first order representations. Such learned redescriptions form the basis of conscious experience. Learning and plasticity are thus constitutive of consciousness. This is what I call the “Radical Plasticity Thesis”. In a sense, this is the enactive perspective, but turned both inwards and (further) outwards. Consciousness involves “signal detection on the mind”; the conscious mind is the brain's (non-conceptual, implicit) theory about itself. Theoretically, RADICAL offers the possibility of unifying Global Workspace Theory with higher-order Thought Theory by showing how the former can be built through mechanisms that flesh out the latter. Empirically, RADICAL aims at testing these ideas in three domains: (1) the perception action loop, (2) the self-other loop, and (3) the inner loop. 20 experiments leveraging behavioural experimentation, brain imaging, and computational modeling are proposed to test and further develop RADICAL. The overarching goal of the project is to characterize the computational principles that differentiate conscious from unconscious cognition, based on a bold, original, and innovative theory in which learning and plasticity play central roles.

2 286 316 €

Start date: 2014-05-01, End date: 2019-04-30