ERC FUNDED PROJECTS

Cells use circuits of interacting proteins to respond to their environment. In the past decades, molecular biology has provided detailed knowledge on the proteins in these circuits and their interactions. To fully understand circuit function requires, in addition to molecular knowledge, new concepts that explain how multiple components work together to perform systems level functions. Our lab has been a leader in defining such concepts, based on combined experimental and theoretical study of well characterized circuits in bacteria and human cells. In this proposal we aim to find novel principles on how circuits resist fluctuations and errors, and how they can be controlled by drugs: (1) Why do key regulatory systems use bifunctional enzymes that catalyze antagonistic reactions (e.g. both kinase and phosphatase)? We will test the role of bifunctional enzymes in making circuits robust to variations in protein levels. (2) Why are some genes regulated by a repressor and others by an activator? We will test this in the context of reduction of errors in transcription control. (3) Are there principles that describe how drugs combine to affect protein dynamics in human cells? We will use a novel dynamic proteomics approach developed in our lab to explore how protein dynamics can be controlled by drug combinations. This research will define principles that unite our understanding of seemingly distinct biological systems, and explain their particular design in terms of systems-level functions. This understanding will help form the basis for a future medicine that rationally controls the state of the cell based on a detailed blueprint of their circuit design, and quantitative principles for the effects of drugs on this circuitry.

2 261 440 €

Start date: 2010-03-01, End date: 2015-02-28

The role of children's behavior and temperament is increasingly acknowledged in family research. Gene-environment Correlation (rGE) processes may account for some child effects, as parents react to children s behavior which is in part genetically influenced (evocative rGE). In addition, passive rGE, in which parenting and children s behavior are correlated through overlapping genetic influences on family members behavior may account in part for the parenting-child behavior relationships. The proposed project will be the first one to directly address these issues with DNA information on family members and quality observational data on parent and child behaviors, following children through early development. Two separate longitudinal studies will investigate the paths from children s genes to their behavior, to the way parents react and modify their parenting towards the child, affecting child development: Study 1 will follow first-time parents from pregnancy through children s early childhood, decoupling parent effect and child effects. Study 2 will follow dizygotic twins and their parents through middle childhood, capitalizing on genetic differences between twins reared by the same parents. We will test the hypothesis that parents' characteristics, such as parenting style and parental attitudes, are associated with children's genetic tendencies. Both parenting and child behaviors will be monitored consecutively, to investigate the co-development of parents and children in an evocative rGE process. Child and parent candidate genes relevant to social behavior, notably those from the dompaminergic and serotonergic systems, will be linked to parents behaviors. Pilot results show children s genes predict parenting, and an important task for the study will be to identify mediators of this effect, such as children s temperament. We will lay the ground for further research into the complexity of gene-environment correlations as children and parents co-develop.

1 443 687 €

Start date: 2010-01-01, End date: 2015-12-31

Sometimes in the sciences there are different yet complementary descriptions for the same object. This extends to the particle-wave duality of quantum mechanics; one mathematical analog of this duality is the Fourier transform. Questions that are difficult when formulated in one language of science may become simple when interpreted in another. The Langlands conjecture posits the existence of a correspondence between problems in arithmetic and in Representation Theory. The Langlands conjecture has only been proven for a limited number of cases, but even this has solved problems such as the famous Fermat conjecture. The aim of this project is to continue study of the "classical" aspects of the Langlands conjecture and to extend the conjecture to the quantum geometric Langlands correspondence, higher-dimensional fields, Kac-Moody groups (with D.Gaitsgory: quantum Langlands correspondence; D.Gaitsgory and E. Hrushevsi: groups over higher-dimensional fields; A. Braverman: Kac-Moody groups; R. Bezrukavnikov, S.Debacker, Y.Varshavsky: classical aspects of the correspondence; A. Berenstein: geometric crystals and crystal bases). The quantum case is much more symmetric than the classical case and can lead in the limit q->0 to new insights into the classical case. The quantum case is also related to the multiple Dirichlet series. New results in the quantum case would lead to progress in understanding important Number Theoretic questions. Extending the Langlands correspondence to groups over higher-dimensional fields could substantially enlarge its applicability. Studying Kac-Moody groups would provide tools for the new important class of L-functions. This progress could lead to a proof of the existence of the analytic continuation of classical L-functions. The geometric Langlands correspondence is closely related to T-symmetry in 4-dimensional gauge theory and the understanding of this relation is important for both Mathematics and Physics.

1 277 060 €

Start date: 2010-01-01, End date: 2014-12-31

80% of the proteome exists in complexes or large macromolecular assemblies. It is accepted that revealing the structure of these protein complexes is a key towards mechanistic understanding of cellular processes. Yet, this might not be sufficient; a higher level of complexity probably exists and protein complexes may not be static and uniform in form and function as thought. A protein complex may actually represent an ensemble of compositionally distinct entities with functional versatility. My main aim is to provide evidence for this conceptual change and to reveal the dynamic architecture of a protein assembly. As a model system, I will investigate the COP9 signalosome (CSN), an evolutionary conserved multisubunit complex, which is involved in a variety of essential functions ranging from cell-cycle progression, DNA-repair and apoptosis. My strategy is based on a comprehensive approach, made up of four main steps; i) Revealing the structural organization of the native complex. ii) Establishing whether the complex has co-existing independent modules that function separately of, or coordinately with the holocomplex. iii) Monitoring in real-time the biogenesis and activation pathway of the complex and developing an approach for shifting its oligomerization equilibrium. iv) Determining the correlation between modularity of the complex and cell cycle progression and comparing its composition in healthy versus cancerous cells. I will integrate genetic, biochemical and structural biology approaches. In particular, I will apply a state of the art mass spectrometry technique, that will enable us to define the stoichiometry, subunit composition, dynamic interactions and structural organization of protein complexes isolated directly from the cellular environment.

1 500 000 €

Start date: 2009-09-01, End date: 2014-08-31