Project acronym COCO
Project The molecular complexity of the complement system
Researcher (PI) Piet Gros
Host Institution (HI) UNIVERSITEIT UTRECHT
Call Details Advanced Grant (AdG), LS1, ERC-2008-AdG
Summary The complement system is a regulatory pathway in mammalian plasma that enables the host to recognize and clear invading pathogens and altered host cells, while protecting healthy host tissue. This regulatory system consists of ~30 large multi-domain plasma and cell-surface proteins, that act in concert through an interplay of proteolysis and complex formations on target membranes. We study the molecular events on membranes that ensure initiation and amplification of the response, protection of host cells and activation of immune responses leading to cell lysis, phagocytosis and B-cell stimulation.
In the past few years, we have resolved the structural details of the large complement proteins involved in the central, aspecific labelling and amplification step; with recent data we revealed the structural basis of the assembly and activity of the protease complex associated with this step. These insights into the central aspecific reaction, and the experiences gained on working with these large multi-domain proteins and complexes, give us an excellent starting point to addres the questions of specificity, protection and activation of immune cells.
The goal of the proposal is to elucidate the multivalent molecular mechanisms of recognition, regulation and immune cell activation of the complement system on target membranes. We will use protein crystallography and electron microscopy to study the interactions and conformational changes involved in protein complex formation, and (single-molecule) fluorescence to resolve the multivalent molecular events, the conformational states and transitions that occur on the membrane. The combined data will provide mechanistic insights into the specifity of immune clearance by the complement system.
Understanding the molecular mechanisms of complement activation and regulation will be instrumental in developing more potent therapeutics to control infections, prevent tissue damage and fight tumours by immunotherapies.
Summary
The complement system is a regulatory pathway in mammalian plasma that enables the host to recognize and clear invading pathogens and altered host cells, while protecting healthy host tissue. This regulatory system consists of ~30 large multi-domain plasma and cell-surface proteins, that act in concert through an interplay of proteolysis and complex formations on target membranes. We study the molecular events on membranes that ensure initiation and amplification of the response, protection of host cells and activation of immune responses leading to cell lysis, phagocytosis and B-cell stimulation.
In the past few years, we have resolved the structural details of the large complement proteins involved in the central, aspecific labelling and amplification step; with recent data we revealed the structural basis of the assembly and activity of the protease complex associated with this step. These insights into the central aspecific reaction, and the experiences gained on working with these large multi-domain proteins and complexes, give us an excellent starting point to addres the questions of specificity, protection and activation of immune cells.
The goal of the proposal is to elucidate the multivalent molecular mechanisms of recognition, regulation and immune cell activation of the complement system on target membranes. We will use protein crystallography and electron microscopy to study the interactions and conformational changes involved in protein complex formation, and (single-molecule) fluorescence to resolve the multivalent molecular events, the conformational states and transitions that occur on the membrane. The combined data will provide mechanistic insights into the specifity of immune clearance by the complement system.
Understanding the molecular mechanisms of complement activation and regulation will be instrumental in developing more potent therapeutics to control infections, prevent tissue damage and fight tumours by immunotherapies.
Max ERC Funding
1 700 000 €
Duration
Start date: 2009-04-01, End date: 2014-03-31
Project acronym DAMAGE
Project DNA damage and the connection with cancer, premature aging and longevity
Researcher (PI) Jan Hendrik Jozef Hoeijmakers
Host Institution (HI) ERASMUS UNIVERSITAIR MEDISCH CENTRUM ROTTERDAM
Call Details Advanced Grant (AdG), LS1, ERC-2008-AdG
Summary We study DNA damage and genome stability and its impact on human health using nucleotide excision repair (NER) as paradigm. Patients with NER defects present a perplexing clinical heterogeneity ranging from extreme cancer predisposition to dramatic neurodevelopmental deficits. To elucidate the underlying mechanism we adopted an integral strategy from gene to patient and contributed to resolving the NER reaction in vitro and its dynamic organization in vivo, using molecular genetics, advanced life cell imaging and photobleaching. Mouse NER mutants revealed an unexpected link between DNA damage and (premature) aging, as strong as the DNA damage-cancer connection. We found a striking correlation between type/severity of the repair defect and degree of premature aging, with some mutants dying of aging in 3 weeks! Pathological and functional analysis and expression profiling confirmed that this is bona fide aging. Conditional mutants allowed targeting accelerated aging to specific organs/stages of development e.g. dramatic aging only in brain. Expression profiling revealed that short-lived repair mutants mount a survival response that attempts to extend lifespan by investing in defenses at the expense of growth. The ambitious objective of this multi-disciplinary proposal is to obtain an integral understanding of the biological/medical impact of DNA damage and the important survival response, with emphasis on rational-based prevention and intervention strategies for cancer and other aging-related diseases using the rapidly aging mouse mutants as tools. Triggering the survival response at adulthood is expected to postpone many aging-related diseases including cancer and to strongly improve quality of life at later age. We already identified compounds that influence rapid aging in mice and demonstrated the potency of the survival response to withstand ischemia reperfusion damage. Thus, this proposal addresses the major medical challenges faced by our society.
Summary
We study DNA damage and genome stability and its impact on human health using nucleotide excision repair (NER) as paradigm. Patients with NER defects present a perplexing clinical heterogeneity ranging from extreme cancer predisposition to dramatic neurodevelopmental deficits. To elucidate the underlying mechanism we adopted an integral strategy from gene to patient and contributed to resolving the NER reaction in vitro and its dynamic organization in vivo, using molecular genetics, advanced life cell imaging and photobleaching. Mouse NER mutants revealed an unexpected link between DNA damage and (premature) aging, as strong as the DNA damage-cancer connection. We found a striking correlation between type/severity of the repair defect and degree of premature aging, with some mutants dying of aging in 3 weeks! Pathological and functional analysis and expression profiling confirmed that this is bona fide aging. Conditional mutants allowed targeting accelerated aging to specific organs/stages of development e.g. dramatic aging only in brain. Expression profiling revealed that short-lived repair mutants mount a survival response that attempts to extend lifespan by investing in defenses at the expense of growth. The ambitious objective of this multi-disciplinary proposal is to obtain an integral understanding of the biological/medical impact of DNA damage and the important survival response, with emphasis on rational-based prevention and intervention strategies for cancer and other aging-related diseases using the rapidly aging mouse mutants as tools. Triggering the survival response at adulthood is expected to postpone many aging-related diseases including cancer and to strongly improve quality of life at later age. We already identified compounds that influence rapid aging in mice and demonstrated the potency of the survival response to withstand ischemia reperfusion damage. Thus, this proposal addresses the major medical challenges faced by our society.
Max ERC Funding
2 000 000 €
Duration
Start date: 2010-01-01, End date: 2014-12-31
Project acronym FRU CIRCUIT
Project Neural basis of Drosophila mating behaviours
Researcher (PI) Barry Dickson
Host Institution (HI) FORSCHUNGSINSTITUT FUR MOLEKULARE PATHOLOGIE GESELLSCHAFT MBH
Call Details Advanced Grant (AdG), LS5, ERC-2008-AdG
Summary How does information processing in neural circuits generate behaviour? Answering this question requires identifying each of the distinct neuronal types that contributes to a behaviour, defining their anatomy and connectivity, and establishing causal relationships between their activity, the activity of other neurons in the circuit, and the behaviour. Here, I propose such an analysis of the neural circuits that guide Drosophila mating behaviours. The distinct mating behaviours of males and females are genetically pre-programmed, yet can also be modified by experience. The set of ~2000 neurons that express the fru gene have been intimately linked to both male and female mating behaviours. This set of neurons includes specific sensory, central, and motor neurons, at least some of which are directly connected. Male-specific fruM isoforms configure this circuit developmentally for male rather than female behaviour. In females, mating triggers a biochemical cascade that reconfigures the circuit for post-mating rather than virgin female behaviour. We estimate that there are ~100 distinct classes of fru neuron. Using genetic and optical tools, we aim to identify each distinct class of fru neuron and to define its anatomy and connectivity. By silencing or activating specific neurons, or changing their genetic sex, we will assess their contributions to male and female behaviours, and how these perturbations impinge on activity patterns in other fru neurons. We also aim to define how a specific experience can modify the physiological properties of these circuits, and how these changes in turn modulate mating behaviour. These studies will define the operating principles of these neural circuits, contributing to a molecules-to-systems explanation of Drosophila s mating behaviours.
Summary
How does information processing in neural circuits generate behaviour? Answering this question requires identifying each of the distinct neuronal types that contributes to a behaviour, defining their anatomy and connectivity, and establishing causal relationships between their activity, the activity of other neurons in the circuit, and the behaviour. Here, I propose such an analysis of the neural circuits that guide Drosophila mating behaviours. The distinct mating behaviours of males and females are genetically pre-programmed, yet can also be modified by experience. The set of ~2000 neurons that express the fru gene have been intimately linked to both male and female mating behaviours. This set of neurons includes specific sensory, central, and motor neurons, at least some of which are directly connected. Male-specific fruM isoforms configure this circuit developmentally for male rather than female behaviour. In females, mating triggers a biochemical cascade that reconfigures the circuit for post-mating rather than virgin female behaviour. We estimate that there are ~100 distinct classes of fru neuron. Using genetic and optical tools, we aim to identify each distinct class of fru neuron and to define its anatomy and connectivity. By silencing or activating specific neurons, or changing their genetic sex, we will assess their contributions to male and female behaviours, and how these perturbations impinge on activity patterns in other fru neurons. We also aim to define how a specific experience can modify the physiological properties of these circuits, and how these changes in turn modulate mating behaviour. These studies will define the operating principles of these neural circuits, contributing to a molecules-to-systems explanation of Drosophila s mating behaviours.
Max ERC Funding
2 492 164 €
Duration
Start date: 2009-07-01, End date: 2013-09-30
Project acronym GEMIS
Project Generalized Homological Mirror Symmetry and Applications
Researcher (PI) Ludmil Katzarkov
Host Institution (HI) UNIVERSITAT WIEN
Call Details Advanced Grant (AdG), PE1, ERC-2008-AdG
Summary Mirror symmetry arose originally in physics, as a duality between $N = 2$ superconformal field theories. Witten formulated a more mathematically accessible version, in terms of topological field theories. Both conformal and topological field theories can be defined axiomatically, but more interestingly, there are several geometric ways of constructing them. A priori, the mirror correspondence is not unique, and it does not necessarily remain within a single class of geometric models. The classical case relates $\sigma$-models, but in a more modern formulation, one has mirror dualities between different Landau-Ginzburg models, as well as between such models and $\sigma$-models; orbifolds should also be included in this. The simplest example would be the function $W: \C \rightarrow \C$, $W(x) = x^{n+1}$, which is self-mirror (up to dividing by the $\bZ/n+1$ symmetry group, in an orbifold sense). While the mathematics of the $\sigma$-model mirror correspondence is familiar by now, generalizations to Landau-Ginzburg theories are only beginning to be understood. Today it is clear that Homologcal Mirror Symmetry (HMS) as a categorical correspondence works and it is time for developing direct geometric applications to classical problems - rationality of algebraic varieties and Hodge conjecture. This the main goal of the proposal. But in order to attack the above problems we need to generalize HMS and explore its connection to new developments in modern Hodge theory. In order to carry the above program we plan to further already working team Vienna, Paris, Moscow, MIT.
Summary
Mirror symmetry arose originally in physics, as a duality between $N = 2$ superconformal field theories. Witten formulated a more mathematically accessible version, in terms of topological field theories. Both conformal and topological field theories can be defined axiomatically, but more interestingly, there are several geometric ways of constructing them. A priori, the mirror correspondence is not unique, and it does not necessarily remain within a single class of geometric models. The classical case relates $\sigma$-models, but in a more modern formulation, one has mirror dualities between different Landau-Ginzburg models, as well as between such models and $\sigma$-models; orbifolds should also be included in this. The simplest example would be the function $W: \C \rightarrow \C$, $W(x) = x^{n+1}$, which is self-mirror (up to dividing by the $\bZ/n+1$ symmetry group, in an orbifold sense). While the mathematics of the $\sigma$-model mirror correspondence is familiar by now, generalizations to Landau-Ginzburg theories are only beginning to be understood. Today it is clear that Homologcal Mirror Symmetry (HMS) as a categorical correspondence works and it is time for developing direct geometric applications to classical problems - rationality of algebraic varieties and Hodge conjecture. This the main goal of the proposal. But in order to attack the above problems we need to generalize HMS and explore its connection to new developments in modern Hodge theory. In order to carry the above program we plan to further already working team Vienna, Paris, Moscow, MIT.
Max ERC Funding
1 060 800 €
Duration
Start date: 2009-01-01, End date: 2013-12-31
