ERC Funded Projects

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  • Rcn
    193418
    Nid
    14273
    Project acronym
    20SComplexity
    Project
    An integrative approach to uncover the multilevel regulation of 20S proteasome degradation
    Host Institution (HI)
    Weizmann Institute Of Science, Israel
    Call details
    Starting Grant (StG), ERC-2014-STG
    Summary
    For many years, the ubiquitin-26S proteasome degradation pathway was considered the primary route for proteasomal degradation. However, it is now becoming clear that proteins can also be targeted for degradation by a ubiquitin-independent mechanism mediated by the core 20S proteasome itself. Although initially believed to be limited to rare exceptions, degradation by the 20S proteasome is now understood to have a wide range of substrates, many of which are key regulatory proteins. Despite its importance, little is known about the mechanisms that control 20S proteasomal degradation, unlike the extensive knowledge acquired over the years concerning degradation by the 26S proteasome. Our overall aim is to reveal the multiple regulatory levels that coordinate the 20S proteasome degradation route. To achieve this goal we will carry out a comprehensive research program characterizing three distinct levels of 20S proteasome regulation: Intra-molecular regulation- Revealing the intrinsic molecular switch that activates the latent 20S proteasome. Inter-molecular regulation- Identifying novel proteins that bind the 20S proteasome to regulate its activity and characterizing their mechanism of function. Cellular regulatory networks- Unraveling the cellular cues and multiple pathways that influence 20S proteasome activity using a novel systematic and unbiased screening approach. Our experimental strategy involves the combination of biochemical approaches with native mass spectrometry, cross-linking and fluorescence measurements, complemented by cell biology analyses and high-throughput screening. Such a multidisciplinary approach, integrating in vitro and in vivo findings, will likely provide the much needed knowledge on the 20S proteasome degradation route. When completed, we anticipate that this work will be part of a new paradigm – no longer perceiving the 20S proteasome mediated degradation as a simple and passive event but rather a tightly regulated and coordinated process.
    Website (HI)
    Max ERC funding
    1,500,000
    Duration
    Start date: 2015-04-01, End date: 2020-03-31
  • Rcn
    101102
    Nid
    10777
    Project acronym
    ABATSYNAPSE
    Project
    Evolution of Alzheimer’s Disease: From dynamics of single synapses to memory loss
    Researcher (PI)
    Inna Slutsky
    Host Institution (HI)
    Tel Aviv University, Israel
    Call details
    Starting Grant (StG), LS5, ERC-2011-StG
    Summary
    A persistent challenge in unravelling mechanisms that regulate memory function is how to bridge the gap between inter-molecular dynamics of single proteins, activity of individual synapses and emerging properties of neuronal circuits. The prototype condition of disintegrating neuronal circuits is Alzheimer’s Disease (AD). Since the early time of Alois Alzheimer at the turn of the 20th century, scientists have been searching for a molecular entity that is in the roots of the cognitive deficits. Although diverse lines of evidence suggest that the amyloid-beta peptide (Abeta) plays a central role in synaptic dysfunctions of AD, several key questions remain unresolved. First, endogenous Abeta peptides are secreted by neurons throughout life, but their physiological functions are largely unknown. Second, experience-dependent physiological mechanisms that initiate the changes in Abeta composition in sporadic, the most frequent form of AD, are unidentified. And finally, molecular mechanisms that trigger Abeta-induced synaptic failure and memory decline remain elusive. To target these questions, I propose to develop an integrative approach to correlate structure and function at the level of single synapses in hippocampal circuits. State-of-the-art techniques will enable the simultaneous real-time visualization of inter-molecular dynamics within signalling complexes and functional synaptic modifications. Utilizing FRET spectroscopy, high-resolution optical imaging, electrophysiology, molecular biology and biochemistry we will determine the casual relationship between ongoing neuronal activity, temporo-spatial dynamics and molecular composition of Abeta, structural rearrangements within the Abeta signalling complexes and plasticity of single synapses and whole networks. The proposed research will elucidate fundamental principles of neuronal circuits function and identify critical steps that initiate primary synaptic dysfunctions at the very early stages of sporadic AD.
    Website (HI)
    Max ERC funding
    2,000,000
    Duration
    Start date: 2011-12-01, End date: 2017-09-30
  • Rcn
    109965
    Nid
    11939
    Project acronym
    ABDESIGN
    Project
    Computational design of novel protein function in antibodies
    Researcher (PI)
    Sarel-Jacob Fleishman
    Host Institution (HI)
    Weizmann Institute Of Science, Israel
    Call details
    Starting Grant (StG), LS1, ERC-2013-StG
    Summary
    We propose to elucidate the structural design principles of naturally occurring antibody complementarity-determining regions (CDRs) and to computationally design novel antibody functions. Antibodies represent the most versatile known system for molecular recognition. Research has yielded many insights into antibody design principles and promising biotechnological and pharmaceutical applications. Still, our understanding of how CDRs encode specific loop conformations lags far behind our understanding of structure-function relationships in non-immunological scaffolds. Thus, design of antibodies from first principles has not been demonstrated. We propose a computational-experimental strategy to address this challenge. We will: (a) characterize the design principles and sequence elements that rigidify antibody CDRs. Natural antibody loops will be subjected to computational modeling, crystallography, and a combined in vitro evolution and deep-sequencing approach to isolate sequence features that rigidify loop backbones; (b) develop a novel computational-design strategy, which uses the >1000 solved structures of antibodies deposited in structure databases to realistically model CDRs and design them to recognize proteins that have not been co-crystallized with antibodies. For example, we will design novel antibodies targeting insulin, for which clinically useful diagnostics are needed. By accessing much larger sequence/structure spaces than are available to natural immune-system repertoires and experimental methods, computational antibody design could produce higher-specificity and higher-affinity binders, even to challenging targets; and (c) develop new strategies to program conformational change in CDRs, generating, e.g., the first allosteric antibodies. These will allow targeting, in principle, of any molecule, potentially revolutionizing how antibodies are generated for research and medicine, providing new insights on the design principles of protein functional sites.
    Website (HI)
    Max ERC funding
    1,499,930
    Duration
    Start date: 2013-09-01, End date: 2018-08-31
  • Rcn
    109822
    Nid
    9299
    Project acronym
    AEROBIC
    Project
    Assessing the Effects of Rising O2 on Biogeochemical Cycles: Integrated Laboratory Experiments and Numerical Simulations
    Researcher (PI)
    Itay Halevy
    Host Institution (HI)
    Weizmann Institute Of Science, Israel
    Call details
    Starting Grant (StG), PE10, ERC-2013-StG
    Summary
    The rise of atmospheric O2 ~2,500 million years ago is one of the most profound transitions in Earth's history. Yet, despite its central role in shaping Earth's surface environment, the cause for the rise of O2 remains poorly understood. Tight coupling between the O2 cycle and the biogeochemical cycles of redox-active elements, such as C, Fe and S, implies radical changes in these cycles before, during and after the rise of O2. These changes, too, are incompletely understood, but have left valuable information encoded in the geological record. This information has been qualitatively interpreted, leaving many aspects of the rise of O2, including its causes and constraints on ocean chemistry before and after it, topics of ongoing research and debate. Here, I outline a research program to address this fundamental question in geochemical Earth systems evolution. The inherently interdisciplinary program uniquely integrates laboratory experiments, numerical models, geological observations, and geochemical analyses. Laboratory experiments and geological observations will constrain unknown parameters of the early biogeochemical cycles, and, in combination with field studies, will validate and refine the use of paleoenvironmental proxies. The insight gained will be used to develop detailed models of the coupled biogeochemical cycles, which will themselves be used to quantitatively understand the events surrounding the rise of O2, and to illuminate the dynamics of elemental cycles in the early oceans. This program is expected to yield novel, quantitative insight into these important events in Earth history and to have a major impact on our understanding of early ocean chemistry and the rise of O2. An ERC Starting Grant will enable me to use the excellent experimental and computational facilities at my disposal, to access the outstanding human resource at the Weizmann Institute of Science, and to address one of the major open questions in modern geochemistry.
    Website (HI)
    Max ERC funding
    1,472,690
    Duration
    Start date: 2013-09-01, End date: 2018-08-31
  • Rcn
    88242
    Nid
    11699
    Project acronym
    AGALT
    Project
    Asymptotic Geometric Analysis and Learning Theory
    Researcher (PI)
    Shahar Mendelson
    Host Institution (HI)
    Technion - Israel Institute Of Technology., Israel
    Call details
    Starting Grant (StG), PE1, ERC-2007-StG
    Summary
    "In a typical learning problem one tries to approximate an unknown function by a function from a given class using random data, sampled according to an unknown measure. In this project we will be interested in parameters that govern the complexity of a learning problem. It turns out that this complexity is determined by the geometry of certain sets in high dimension that are connected to the given class (random coordinate projections of the class). Thus, one has to understand the structure of these sets as a function of the dimension - which is given by the cardinality of the random sample. The resulting analysis leads to many theoretical questions in Asymptotic Geometric Analysis, Probability (most notably, Empirical Processes Theory) and Combinatorics, which are of independent interest beyond the application to Learning Theory. Our main goal is to describe the role of various complexity parameters involved in a learning problem, to analyze the connections between them and to investigate the way they determine the geometry of the relevant high dimensional sets. Some of the questions we intend to tackle are well known open problems and making progress towards their solution will have a significant theoretical impact. Moreover, this project should lead to a more complete theory of learning and is likely to have some practical impact, for example, in the design of more efficient learning algorithms."
    Website (HI)
    Max ERC funding
    750,000
    Duration
    Start date: 2009-03-01, End date: 2014-02-28
  • Rcn
    110804
    Nid
    11419
    Project acronym
    AMD
    Project
    Algorithmic Mechanism Design: Beyond Truthful Mechanisms
    Researcher (PI)
    Michal Feldman
    Host Institution (HI)
    Tel Aviv University, Israel
    Call details
    Starting Grant (StG), PE6, ERC-2013-StG
    Summary
    "The first decade of Algorithmic Mechanism Design (AMD) concentrated, very successfully, on the design of truthful mechanisms for the allocation of resources among agents with private preferences. Truthful mechanisms are ones that incentivize rational users to report their preferences truthfully. Truthfulness, however, for all its theoretical appeal, suffers from several inherent limitations, mainly its high communication and computation complexities. It is not surprising, therefore, that practical applications forego truthfulness and use simpler mechanisms instead. Simplicity in itself, however, is not sufficient, as any meaningful mechanism should also have some notion of fairness; otherwise agents will stop using it over time. In this project I plan to develop an innovative AMD theoretical framework that will go beyond truthfulness and focus instead on the natural themes of simplicity and fairness, in addition to computational tractability. One of my primary goals will be the design of simple and fair poly-time mechanisms that perform at near optimal levels with respect to important economic objectives such as social welfare and revenue. To this end, I will work toward providing precise definitions of simplicity and fairness and quantifying the effects of these restrictions on the performance levels that can be obtained. A major challenge in the evaluation of non-truthful mechanisms is defining a reasonable behavior model that will enable their evaluation. The success of this project could have a broad impact on Europe and beyond, as it would guide the design of natural mechanisms for markets of tens of billions of dollars in revenue, such as online advertising, or sales of wireless frequencies. The timing of this project is ideal, as the AMD field is now sufficiently mature to lead to a breakthrough and at the same time young enough to be receptive to new approaches and themes."
    Website (HI)
    Max ERC funding
    1,394,600
    Duration
    Start date: 2013-11-01, End date: 2018-10-31
  • Rcn
    185596
    Nid
    11991
    Project acronym
    APARTHEID-STOPS
    Project
    "Apartheid-- The Global Itinerary: South African Cultural Formations in Transnational Circulation, 1948-1990"
    Researcher (PI)
    Louise Bethlehem
    Host Institution (HI)
    The Hebrew University Of Jerusalem, Israel
    Call details
    Consolidator Grants (CoG), SH5, ERC-2013-CoG
    Summary
    "This proposal proceeds from an anomaly. Apartheid routinely breached the separation that it names. Whereas the South African regime was deeply isolationist in international terms, new research links it to the Cold War and decolonization. Yet this trend does not consider sufficiently that the global contest over the meaning of apartheid and resistance to it occurs on the terrain of culture. My project argues that studying the global circulation of South African cultural formations in the apartheid era provides novel historiographic leverage over Western liberalism during the Cold War. It recasts apartheid as an apparatus of transnational cultural production, turning existing historiography inside out. This study seeks: • To provide the first systematic account of the deterritorialization of “apartheid”—as political signifier and as apparatus generating circuits of transnational cultural production. • To analyze these itinerant cultural formations across media and national borders, articulating new intersections. • To map the itineraries of major South African exiles, where exile is taken to be a system of interlinked circuits of affiliation and cultural production. • To revise the historiography of states other than South Africa through the lens of deterritorialized apartheid-era formations at their respective destinations. • To show how apartheid reveals contradictions within Western liberalism during the Cold War, with special reference to racial inequality. Methodologically, I introduce the model of thick convergence to analyze three periods: 1. Kliptown & Bandung: Novel possibilities, 1948-1960. 2. Sharpeville & Memphis: Drumming up resistance, 1960-1976. 3. From Soweto to Berlin: Spectacle at the barricades, 1976-1990. Each explores a cultural dominant in the form of texts, soundscapes or photographs. My work stands at the frontier of transnational research, furnishing powerful new insights into why South Africa matters on the stage of global history."
    Website (HI)
    Max ERC funding
    1,861,238
    Duration
    Start date: 2014-05-01, End date: 2019-04-30
  • Rcn
    101427
    Nid
    10480
    Project acronym
    ARISE
    Project
    The Ecology of Antibiotic Resistance
    Researcher (PI)
    Roy Kishony
    Host Institution (HI)
    Technion - Israel Institute Of Technology, Israel
    Call details
    Starting Grant (StG), LS8, ERC-2011-StG
    Summary
    Main goal. We aim to understand the puzzling coexistence of antibiotic-resistant and antibiotic-sensitive species in natural soil environments, using novel quantitative experimental techniques and mathematical analysis. The ecological insights gained will be translated into novel treatment strategies for combating antibiotic resistance. Background. Microbial soil ecosystems comprise communities of species interacting through copious secretion of antibiotics and other chemicals. Defence mechanisms, i.e. resistance to antibiotics, are ubiquitous in these wild communities. However, in sharp contrast to clinical settings, resistance does not take over the population. Our hypothesis is that the ecological setting provides natural mechanisms that keep antibiotic resistance in check. We are motivated by our recent finding that specific antibiotic combinations can generate selection against resistance and that soil microbial strains produce compounds that directly target antibiotic resistant mechanisms. Approaches. We will: (1) Isolate natural bacterial species from individual grains of soil, characterize their ability to produce and resist antibiotics and identify the spatial scale for correlations between resistance and production. (2) Systematically measure interactions between species and identify interaction patterns enriched in co-existing communities derived from the same grain of soil. (3) Introducing fluorescently-labelled resistant and sensitive strains into natural soil, we will measure the fitness cost and benefit of antibiotic resistance in situ and identify natural compounds that select against resistance. (4) Test whether such “selection-inverting” compounds can slow evolution of resistance to antibiotics in continuous culture experiments. Conclusions. These findings will provide insights into the ecological processes that keep antibiotic resistance in check, and will suggest novel antimicrobial treatment strategies.
    Website (HI)
    Max ERC funding
    1,900,000
    Duration
    Start date: 2012-09-01, End date: 2018-08-31
  • Rcn
    198776
    Nid
    14857
    Project acronym
    ARRAY SEQ
    Project
    Array-tagged single cell gene expression by parallel linear RNA amplification and sequencing
    Host Institution (HI)
    Technion - Israel Institute Of Technology, Israel
    Call details
    Proof of Concept (PoC), ERC-2015-PoC
    Summary
    In many biomedical research and clinical applications it would be tremendously useful to know the gene expression profile of each and every cell in a sample, be it a blood sample or tumor. At present, the most advanced single-cell technologies are limited to a few thousand cells by a laborious and expensive approach. We have invented a method allowing the determination of the transcriptomes of millions of cells in parallel, using array-based technique for tagging single cells. The protocol combines our previously published protocol for single cell transcriptomics – CEL-Seq – with a new membrane based system for capturing single cells and a DNA microarray for differentially tagging each cell in the membrane. If further developed into a commercial platform, our method could have tremendous impact on clinical and research transcriptomics. Our method requires no expensive equipment, low amounts of reagents and little hands-on, making it unlike any available protocol for single cell analysis. Our method also has great versatility as it can be used for analyzing up to a million cells, but can also be easily scaled down to several hundreds, promising to make it the state of the art protocol for any lab interested in single cell biology. Our method thus represents a game-changer because it completely reinvents the scale under which cells can be examined – affordably and without a need for expensive instruments – by at least three orders of magnitude. The aim of this project is to establish a user-friendly platform for our method that could be commercially available in the coming years. The developed platform will facilitate a large-scale ability to query cells; the breadth of possible research and personal medicine applications is unimaginable at present.
    Website (HI)
    Max ERC funding
    150,000
    Duration
    Start date: 2015-09-01, End date: 2017-02-28
  • Rcn
    185611
    Nid
    10739
    Project acronym
    AXONGROWTH
    Project
    Systematic analysis of the molecular mechanisms underlying axon growth during development and following injury
    Researcher (PI)
    Oren Schuldiner
    Host Institution (HI)
    Weizmann Institute Of Science, Israel
    Call details
    Consolidator Grants (CoG), LS5, ERC-2013-CoG
    Summary
    Axon growth potential declines during development, contributing to the lack of effective regeneration in the adult central nervous system. What determines the intrinsic growth potential of neurites, and how such growth is regulated during development, disease and following injury is a fundamental question in neuroscience. Although multiple lines of evidence indicate that intrinsic growth capability is genetically encoded, its nature remains poorly defined. Neuronal remodeling of the Drosophila mushroom body offers a unique opportunity to study the mechanisms of various types of axon degeneration and growth. We have recently demonstrated that regrowth of axons following developmental pruning is not only distinct from initial outgrowth but also shares molecular similarities with regeneration following injury. In this proposal we combine state of the art tools from genomics, functional genetics and microscopy to perform a comprehensive study of the mechanisms underlying axon growth during development and following injury. First, we will combine genetic, biochemical and genomic studies to gain a mechanistic understanding of the developmental regrowth program. Next, we will perform extensive transcriptomic analyses and comparisons aimed at defining the genetic programs involved in initial axon growth, developmental regrowth, and regeneration following injury. Finally, we will harness the genetic power of Drosophila to perform a comprehensive functional analysis of genes and pathways, those previously known and new ones that we will discover, in various neurite growth paradigms. Importantly, these functional assays will be performed in the same organism, allowing us to use identical genetic mutations across our analyses. To this end, our identification of a new genetic program regulating developmental axon regrowth, together with emerging tools in genomics, places us in a unique position to gain a broad understanding of axon growth during development and following injury.
    Website (HI)
    Max ERC funding
    2,000,000
    Duration
    Start date: 2014-03-01, End date: 2019-02-28