Project acronym ADIMMUNE
Project Decoding interactions between adipose tissue immune cells, metabolic function, and the intestinal microbiome in obesity
Researcher (PI) Eran Elinav
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Country Israel
Call Details Consolidator Grant (CoG), LS6, ERC-2018-COG
Summary Obesity and its metabolic co-morbidities have given rise to a rapidly expanding ‘metabolic syndrome’ pandemic affecting
hundreds of millions of individuals worldwide. The integrative genetic and environmental causes of the obesity pandemic
remain elusive. White adipose tissue (WAT)-resident immune cells have recently been highlighted as important factors
contributing to metabolic complications. However, a comprehensive understanding of the regulatory circuits governing their
function and the cell type-specific mechanisms by which they contribute to the development of metabolic syndrome is
lacking. Likewise, the gut microbiome has been suggested as a critical regulator of obesity, but the bacterial species and
metabolites that influence WAT inflammation are entirely unknown.
We propose to use our recently developed high-throughput genomic and gnotobiotic tools, integrated with CRISPR-mediated interrogation of gene function, microbial culturomics, and in-vivo metabolic analysis in newly generated mouse models, in order to achieve a new level of molecular understanding of how WAT immune cells integrate environmental cues into their crosstalk with organismal metabolism, and to explore the microbial contributions to the molecular etiology of WAT inflammation in the pathogenesis of diet-induced obesity. Specifically, we aim to (a) decipher the global regulatory landscape and interaction networks of WAT hematopoietic cells at the single-cell level, (b) identify new mediators of WAT immune cell contributions to metabolic homeostasis, and (c) decode how host-microbiome communication shapes the development of WAT inflammation and obesity.
Unraveling the principles of WAT immune cell regulation and their amenability to change by host-microbiota interactions
may lead to a conceptual leap forward in our understanding of metabolic physiology and disease. Concomitantly, it may
generate a platform for microbiome-based personalized therapy against obesity and its complications.
Summary
Obesity and its metabolic co-morbidities have given rise to a rapidly expanding ‘metabolic syndrome’ pandemic affecting
hundreds of millions of individuals worldwide. The integrative genetic and environmental causes of the obesity pandemic
remain elusive. White adipose tissue (WAT)-resident immune cells have recently been highlighted as important factors
contributing to metabolic complications. However, a comprehensive understanding of the regulatory circuits governing their
function and the cell type-specific mechanisms by which they contribute to the development of metabolic syndrome is
lacking. Likewise, the gut microbiome has been suggested as a critical regulator of obesity, but the bacterial species and
metabolites that influence WAT inflammation are entirely unknown.
We propose to use our recently developed high-throughput genomic and gnotobiotic tools, integrated with CRISPR-mediated interrogation of gene function, microbial culturomics, and in-vivo metabolic analysis in newly generated mouse models, in order to achieve a new level of molecular understanding of how WAT immune cells integrate environmental cues into their crosstalk with organismal metabolism, and to explore the microbial contributions to the molecular etiology of WAT inflammation in the pathogenesis of diet-induced obesity. Specifically, we aim to (a) decipher the global regulatory landscape and interaction networks of WAT hematopoietic cells at the single-cell level, (b) identify new mediators of WAT immune cell contributions to metabolic homeostasis, and (c) decode how host-microbiome communication shapes the development of WAT inflammation and obesity.
Unraveling the principles of WAT immune cell regulation and their amenability to change by host-microbiota interactions
may lead to a conceptual leap forward in our understanding of metabolic physiology and disease. Concomitantly, it may
generate a platform for microbiome-based personalized therapy against obesity and its complications.
Max ERC Funding
2 000 000 €
Duration
Start date: 2019-03-01, End date: 2024-02-29
Project acronym Agglomerates
Project Infinite Protein Self-Assembly in Health and Disease
Researcher (PI) Emmanuel Doram LEVY
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Country Israel
Call Details Consolidator Grant (CoG), LS2, ERC-2018-COG
Summary Understanding how proteins respond to mutations is of paramount importance to biology and disease. While protein stability and misfolding have been instrumental in rationalizing the impact of mutations, we recently discovered that an alternative route is also frequent, where mutations at the surface of symmetric proteins trigger novel self-interactions that lead to infinite self-assembly. This mechanism can be involved in disease, as in sickle-cell anemia, but may also serve in adaptation. Importantly, it differs fundamentally from aggregation, because misfolding does not drive it. Thus, we term it “agglomeration”. The ease with which agglomeration can occur, even by single point mutations, shifts the paradigm of how quickly new protein assemblies can emerge, both in health and disease. This prompts us to determine the basic principles of protein agglomeration and explore its implications in cell physiology and human disease.
We propose an interdisciplinary research program bridging atomic and cellular scales to explore agglomeration in three aims: (i) Map the landscape of protein agglomeration in response to mutation in endogenous yeast proteins; (ii) Characterize how yeast physiology impacts agglomeration by changes in gene expression or cell state, and, conversely, how protein agglomerates impact yeast fitness. (iii) Analyze agglomeration in relation to human disease via two approaches. First, by predicting single nucleotide polymorphisms that trigger agglomeration, prioritizing them using knowledge from Aims 1 & 2, and characterizing them experimentally. Second, by providing a proof-of-concept that agglomeration can be exploited in drug design, whereby drugs induce its formation, like mutations can do.
Overall, through this research, we aim to establish agglomeration as a paradigm for protein assembly, with implications for our understanding of evolution, physiology, and disease.
Summary
Understanding how proteins respond to mutations is of paramount importance to biology and disease. While protein stability and misfolding have been instrumental in rationalizing the impact of mutations, we recently discovered that an alternative route is also frequent, where mutations at the surface of symmetric proteins trigger novel self-interactions that lead to infinite self-assembly. This mechanism can be involved in disease, as in sickle-cell anemia, but may also serve in adaptation. Importantly, it differs fundamentally from aggregation, because misfolding does not drive it. Thus, we term it “agglomeration”. The ease with which agglomeration can occur, even by single point mutations, shifts the paradigm of how quickly new protein assemblies can emerge, both in health and disease. This prompts us to determine the basic principles of protein agglomeration and explore its implications in cell physiology and human disease.
We propose an interdisciplinary research program bridging atomic and cellular scales to explore agglomeration in three aims: (i) Map the landscape of protein agglomeration in response to mutation in endogenous yeast proteins; (ii) Characterize how yeast physiology impacts agglomeration by changes in gene expression or cell state, and, conversely, how protein agglomerates impact yeast fitness. (iii) Analyze agglomeration in relation to human disease via two approaches. First, by predicting single nucleotide polymorphisms that trigger agglomeration, prioritizing them using knowledge from Aims 1 & 2, and characterizing them experimentally. Second, by providing a proof-of-concept that agglomeration can be exploited in drug design, whereby drugs induce its formation, like mutations can do.
Overall, through this research, we aim to establish agglomeration as a paradigm for protein assembly, with implications for our understanding of evolution, physiology, and disease.
Max ERC Funding
2 574 819 €
Duration
Start date: 2019-04-01, End date: 2024-09-30
Project acronym AMPS
Project Ancient Mesopotamian Priestly Scholasticism in the First Millennium BCE
Researcher (PI) Uri Gabbay
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Country Israel
Call Details Consolidator Grant (CoG), SH5, ERC-2020-COG
Summary The scholarly texts of ancient Mesopotamia in the first millennium BCE, specifically commentaries written in Akkadian on cuneiform tablets, were the work of priests who also performed cultic activities in the temple. The proposed project seeks to demonstrate how these scholarly and cultic activities were interrelated and how they shaped the self-identity of the priestly-scholarly community that was in charge of both. The project thus aims to bridge the gap between the study of intellectual history and the study of priesthood in ancient Mesopotamia, which are treated as two separate fields in Assyriology.
The project innovatively treats Mesopotamian scholarship and Mesopotamian priesthood as complementary aspects of one phenomenon: “scholasticism.” This concept, which originally referred to the scholarly activities of Catholic priests in the Middle Ages, has recently been applied to the study of non-European communities of priestly scholars with great success. Using the scholastic model to study the priestly-scholarly community of ancient Mesopotamia will reveal the intricate connections between the ritual and textual activities of this community and illuminate the holistic and systematic worldview of its members.
Combining traditional philology and the comparative approach, the project investigates how, like other scholastic communities, the scholar-priests of ancient Mesopotamia “internalized” the liturgical texts they studied and performed, how they attributed authority to these texts, and how their study of the liturgical corpus generated new exegetical texts. Key points of comparison between the scholar-priests of ancient Mesopotamia and various ancient and contemporary scholastic communities include their interest in language, textual authority, commentaries, and rituals. By applying the comparative method to the study of cuneiform tablets, the project aims to reconstruct the social, religious, and intellectual reality in which they were written.
Summary
The scholarly texts of ancient Mesopotamia in the first millennium BCE, specifically commentaries written in Akkadian on cuneiform tablets, were the work of priests who also performed cultic activities in the temple. The proposed project seeks to demonstrate how these scholarly and cultic activities were interrelated and how they shaped the self-identity of the priestly-scholarly community that was in charge of both. The project thus aims to bridge the gap between the study of intellectual history and the study of priesthood in ancient Mesopotamia, which are treated as two separate fields in Assyriology.
The project innovatively treats Mesopotamian scholarship and Mesopotamian priesthood as complementary aspects of one phenomenon: “scholasticism.” This concept, which originally referred to the scholarly activities of Catholic priests in the Middle Ages, has recently been applied to the study of non-European communities of priestly scholars with great success. Using the scholastic model to study the priestly-scholarly community of ancient Mesopotamia will reveal the intricate connections between the ritual and textual activities of this community and illuminate the holistic and systematic worldview of its members.
Combining traditional philology and the comparative approach, the project investigates how, like other scholastic communities, the scholar-priests of ancient Mesopotamia “internalized” the liturgical texts they studied and performed, how they attributed authority to these texts, and how their study of the liturgical corpus generated new exegetical texts. Key points of comparison between the scholar-priests of ancient Mesopotamia and various ancient and contemporary scholastic communities include their interest in language, textual authority, commentaries, and rituals. By applying the comparative method to the study of cuneiform tablets, the project aims to reconstruct the social, religious, and intellectual reality in which they were written.
Max ERC Funding
1 959 968 €
Duration
Start date: 2021-10-01, End date: 2026-09-30
Project acronym AntiViralEvo
Project Unravelling the evolution of antiviral sensors and response systems in animals using the phylum Cnidaria
Researcher (PI) Yehu Moran
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Country Israel
Call Details Consolidator Grant (CoG), LS8, ERC-2019-COG
Summary Viruses are absolute parasites as their replication depends on biochemical systems of their host. Because viral infections reduce the fitness of the host organism, hosts and viruses have been tangled in an evolutionary arms race for survival from the very beginning of life. As the immune system allows organisms to identify and eliminate viral infections, it is of pivotal importance for host fitness. In vertebrates, the antiviral immunity is heavily based on the interferon pathway that enables infected cells to alert neighbouring cells against incoming infection and recruits cells of the immune system to battle the virus. However, in the case of invertebrates, which lack interferons, the antiviral immunity is believed to be based mostly on an RNA interference (RNAi) that cleaves viral RNA. Until now, the recognition mechanism and mode of action of such systems were studied mostly in vertebrates, insects and nematodes. From this limited phyletic sampling, it is impossible to deduce what was the original mode of action of these systems in their last common ancestor and how antiviral immunity was triggered in early animals. To attain novel insights into the early evolution of this crucial system, I propose to study it in an outgroup: the sea anemone Nematostella vectensis, a representative model species of Cnidaria, a phylum that diverged approximately 600 million years ago from the rest of animals. Beyond its key phyletic position, Nematostella is a tractable lab model with available advanced molecular and gene manipulation tools making it an excellent comparative model. I will harness these tools to decipher the cnidarian system for battling RNA viruses and answer the outstanding questions regarding the evolution of antiviral immunity and its ancestral state in animals. My preliminary results put in question the textbook dichotomy between the antiviral immune systems of vertebrates and invertebrates as I find active components of both systems in Nematostella.
Summary
Viruses are absolute parasites as their replication depends on biochemical systems of their host. Because viral infections reduce the fitness of the host organism, hosts and viruses have been tangled in an evolutionary arms race for survival from the very beginning of life. As the immune system allows organisms to identify and eliminate viral infections, it is of pivotal importance for host fitness. In vertebrates, the antiviral immunity is heavily based on the interferon pathway that enables infected cells to alert neighbouring cells against incoming infection and recruits cells of the immune system to battle the virus. However, in the case of invertebrates, which lack interferons, the antiviral immunity is believed to be based mostly on an RNA interference (RNAi) that cleaves viral RNA. Until now, the recognition mechanism and mode of action of such systems were studied mostly in vertebrates, insects and nematodes. From this limited phyletic sampling, it is impossible to deduce what was the original mode of action of these systems in their last common ancestor and how antiviral immunity was triggered in early animals. To attain novel insights into the early evolution of this crucial system, I propose to study it in an outgroup: the sea anemone Nematostella vectensis, a representative model species of Cnidaria, a phylum that diverged approximately 600 million years ago from the rest of animals. Beyond its key phyletic position, Nematostella is a tractable lab model with available advanced molecular and gene manipulation tools making it an excellent comparative model. I will harness these tools to decipher the cnidarian system for battling RNA viruses and answer the outstanding questions regarding the evolution of antiviral immunity and its ancestral state in animals. My preliminary results put in question the textbook dichotomy between the antiviral immune systems of vertebrates and invertebrates as I find active components of both systems in Nematostella.
Max ERC Funding
1 998 750 €
Duration
Start date: 2020-05-01, End date: 2025-04-30
Project acronym ANTSolve
Project A multi-scale perspective into collective problem solving in ants
Researcher (PI) Ofer Feinerman
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Country Israel
Call Details Consolidator Grant (CoG), LS8, ERC-2017-COG
Summary Cognition improves an animal’s ability to tune its responses to environmental conditions. In group living animals, communication works to form a collective cognition that expands the group’s abilities beyond those of individuals. Despite much research, to date, there is little understanding of how collective cognition emerges within biological ensembles. A major obstacle towards such an understanding is the rarity of comprehensive multi-scale empirical data of these complex systems.
We have demonstrated cooperative load transport by ants to be an ideal system to study the emergence of cognition. Similar to other complex cognitive systems, the ants employ high levels of emergence to achieve efficient problem solving over a large range of scenarios. Unique to this system, is its extreme amenability to experimental measurement and manipulation where internal conflicts map to forces, abstract decision making is reflected in direction changes, and future planning manifested in pheromone trails. This allows for an unprecedentedly detailed, multi-scale empirical description of the moment-to-moment unfolding of sophisticated cognitive processes.
This proposal is aimed at materializing this potential to the full. We will examine the ants’ problem solving capabilities under a variety of environmental challenges. We will expose the underpinning rules on the different organizational scales, the flow of information between them, and their relative contributions to collective performance. This will allow for empirical comparisons between the ‘group’ and the ‘sum of its parts’ from which we will quantify the level of emergence in this system. Using the language of information, we will map the boundaries of this group’s collective cognition and relate them to the range of habitable environmental niches. Moreover, we will generalize these insights to formulate a new paradigm of emergence in biological groups opening new horizons in the study of cognitive processes in general.
Summary
Cognition improves an animal’s ability to tune its responses to environmental conditions. In group living animals, communication works to form a collective cognition that expands the group’s abilities beyond those of individuals. Despite much research, to date, there is little understanding of how collective cognition emerges within biological ensembles. A major obstacle towards such an understanding is the rarity of comprehensive multi-scale empirical data of these complex systems.
We have demonstrated cooperative load transport by ants to be an ideal system to study the emergence of cognition. Similar to other complex cognitive systems, the ants employ high levels of emergence to achieve efficient problem solving over a large range of scenarios. Unique to this system, is its extreme amenability to experimental measurement and manipulation where internal conflicts map to forces, abstract decision making is reflected in direction changes, and future planning manifested in pheromone trails. This allows for an unprecedentedly detailed, multi-scale empirical description of the moment-to-moment unfolding of sophisticated cognitive processes.
This proposal is aimed at materializing this potential to the full. We will examine the ants’ problem solving capabilities under a variety of environmental challenges. We will expose the underpinning rules on the different organizational scales, the flow of information between them, and their relative contributions to collective performance. This will allow for empirical comparisons between the ‘group’ and the ‘sum of its parts’ from which we will quantify the level of emergence in this system. Using the language of information, we will map the boundaries of this group’s collective cognition and relate them to the range of habitable environmental niches. Moreover, we will generalize these insights to formulate a new paradigm of emergence in biological groups opening new horizons in the study of cognitive processes in general.
Max ERC Funding
2 000 000 €
Duration
Start date: 2018-06-01, End date: 2023-05-31
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
Country Israel
Call Details Consolidator Grant (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.
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.
Max ERC Funding
1 861 238 €
Duration
Start date: 2014-05-01, End date: 2019-04-30
Project acronym ATTO-GRAM
Project Attosecond Gated Holography
Researcher (PI) Nirit DUDOVICH
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Country Israel
Call Details Consolidator Grant (CoG), PE2, ERC-2019-COG
Summary Strong-field-driven electric currents in condensed-matter systems open new frontiers in manipulating electronic and optical properties on petahertz frequency scales. In this regime, new challenges arise as the role of the band structure and the quantum nature of ultrafast electron-hole dynamics have yet to be resolved. While petahertz spectroscopy and control of condensed-matter systems holds great potential, revealing the underlying attosecond (1 attosecond – 10(-18) second) dynamics of electrons in solids is still in its infancy.
The proposed research aims at the development of a state-of-the-art attosecond metrology scheme that integrates the concept of holography with attosecond gating. Attosecond-gated holography will provide direct insight into the instantaneous evolution of the complex quantum wavefunctions in solid-state systems. This scheme will enable us to follow the electron-hole wavepacket evolution during ultrafast band structure deformation, probing a range of fundamental processes – from sub-cycle phase transitions to ultrafast dynamics in correlated systems. In ATTO-GRAM, we will establish attosecond-gated holography and then apply it to study field-induced transient band structures, resolve electron-hole dynamics during lattice deformation and reveal attosecond phenomena in strongly correlated systems.
Integrating state-of-the-art experimental schemes, supported by advanced theoretical analysis, will lead to the discoveries of new phenomena previously deemed inaccessible. The impact of the proposed research reaches beyond attosecond metrology – opening new routes in the establishment of compact solid-state extreme ultraviolet sources, petahertz electronics and optically induced metamaterials.
Summary
Strong-field-driven electric currents in condensed-matter systems open new frontiers in manipulating electronic and optical properties on petahertz frequency scales. In this regime, new challenges arise as the role of the band structure and the quantum nature of ultrafast electron-hole dynamics have yet to be resolved. While petahertz spectroscopy and control of condensed-matter systems holds great potential, revealing the underlying attosecond (1 attosecond – 10(-18) second) dynamics of electrons in solids is still in its infancy.
The proposed research aims at the development of a state-of-the-art attosecond metrology scheme that integrates the concept of holography with attosecond gating. Attosecond-gated holography will provide direct insight into the instantaneous evolution of the complex quantum wavefunctions in solid-state systems. This scheme will enable us to follow the electron-hole wavepacket evolution during ultrafast band structure deformation, probing a range of fundamental processes – from sub-cycle phase transitions to ultrafast dynamics in correlated systems. In ATTO-GRAM, we will establish attosecond-gated holography and then apply it to study field-induced transient band structures, resolve electron-hole dynamics during lattice deformation and reveal attosecond phenomena in strongly correlated systems.
Integrating state-of-the-art experimental schemes, supported by advanced theoretical analysis, will lead to the discoveries of new phenomena previously deemed inaccessible. The impact of the proposed research reaches beyond attosecond metrology – opening new routes in the establishment of compact solid-state extreme ultraviolet sources, petahertz electronics and optically induced metamaterials.
Max ERC Funding
2 000 000 €
Duration
Start date: 2020-01-01, End date: 2024-12-31
Project acronym AutoCAb
Project Automated computational design of site-targeted repertoires of camelid antibodies
Researcher (PI) Sarel-Jacob FLEISHMAN
Host Institution (HI) WEIZMANN INSTITUTE OF SCIENCE
Country Israel
Call Details Consolidator Grant (CoG), LS9, ERC-2018-COG
Summary We propose to develop the first high-throughput strategy to design, synthesize, and screen repertoires comprising millions of single-domain camelid antibodies (VHH) that target desired protein surfaces. Each VHH will be individually designed for high stability and target-site affinity. We will leverage recent methods developed by our lab for designing stable, specific, and accurate backbones at interfaces, the advent of massive and affordable custom-DNA oligo synthesis, and machine learning methods to accomplish the following aims:
Aim 1: Establish a completely automated computational pipeline that uses Rosetta to design millions of VHHs targeting desired protein surfaces. The variable regions in each design will be encoded in DNA oligo pools, which will be assembled to generate the entire site-targeted repertoire. We will then use high-throughput binding screens followed by deep sequencing to characterize the designs’ target-site affinity and isolate high-affinity binders.
Aim 2: Develop an epitope-focusing strategy that designs several variants of a target antigen, each of which encodes dozens of radical surface mutations outside the target site to disrupt potential off-target site binding. The designs will be used to isolate site-targeting binders from repertoires of Aim 1.
Each high-throughput screen will provide unprecedented experimental data on target-site affinity in millions of individually designed VHHs.
Aim 3: Use machine learning methods to infer combinations of molecular features that distinguish high-affinity binders from non binders. These will be encoded in subsequent designed repertoires, leading to a continuous “learning loop” of methods for high-affinity, site-targeted binding.
AutoCAb’s interdisciplinary strategy will thus lead to deeper understanding of and new general methods for designing stable, high-affinity, site-targeted antibodies, potentially revolutionizing binder and inhibitor discovery in basic and applied biomedical research.
Summary
We propose to develop the first high-throughput strategy to design, synthesize, and screen repertoires comprising millions of single-domain camelid antibodies (VHH) that target desired protein surfaces. Each VHH will be individually designed for high stability and target-site affinity. We will leverage recent methods developed by our lab for designing stable, specific, and accurate backbones at interfaces, the advent of massive and affordable custom-DNA oligo synthesis, and machine learning methods to accomplish the following aims:
Aim 1: Establish a completely automated computational pipeline that uses Rosetta to design millions of VHHs targeting desired protein surfaces. The variable regions in each design will be encoded in DNA oligo pools, which will be assembled to generate the entire site-targeted repertoire. We will then use high-throughput binding screens followed by deep sequencing to characterize the designs’ target-site affinity and isolate high-affinity binders.
Aim 2: Develop an epitope-focusing strategy that designs several variants of a target antigen, each of which encodes dozens of radical surface mutations outside the target site to disrupt potential off-target site binding. The designs will be used to isolate site-targeting binders from repertoires of Aim 1.
Each high-throughput screen will provide unprecedented experimental data on target-site affinity in millions of individually designed VHHs.
Aim 3: Use machine learning methods to infer combinations of molecular features that distinguish high-affinity binders from non binders. These will be encoded in subsequent designed repertoires, leading to a continuous “learning loop” of methods for high-affinity, site-targeted binding.
AutoCAb’s interdisciplinary strategy will thus lead to deeper understanding of and new general methods for designing stable, high-affinity, site-targeted antibodies, potentially revolutionizing binder and inhibitor discovery in basic and applied biomedical research.
Max ERC Funding
2 337 500 €
Duration
Start date: 2019-01-01, End date: 2023-12-31
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
Country Israel
Call Details Consolidator Grant (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.
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.
Max ERC Funding
2 000 000 €
Duration
Start date: 2014-03-01, End date: 2019-02-28
Project acronym BEHAVIOME
Project Aggression and the Gut Microbiome
Researcher (PI) Omry Koren
Host Institution (HI) BAR ILAN UNIVERSITY
Country Israel
Call Details Consolidator Grant (CoG), LS4, ERC-2020-COG
Summary Aggression is one of the most important social behaviors in nature for procreation and survival. However, understanding the underlying pathways and networks leading to aggression remains a major challenge. Although there has been some progress deciphering genetic factors and neural mechanisms influencing aggression, the precise networks and environmental factors controlling aggression remain a mystery. In this proposal, we suggest the novel concept that host aggression may be regulated in part by the microbiota. We and others have recently linked the gut microbiota, the overall constellation of microorganisms residing within our gut, to behaviors such as risk taking, mating and sexual behavior, as well as hormone production, regulation, and secretion. Here, we aim to characterize the effects of antibiotics, germ-free animal models, and specific microbes on aggression in flies and mice. We further hypothesize that these processes are mediated by pheromones, bacterial and host gene products, and host brain hormones, and will therefore test the involvement of these factors. Considering the microbiota as a novel element regulating aggression is an audacious concept. However, we have demonstrated in a preliminary study that elimination of the gut microbiota significantly raises aggression levels in both D. melanogaster and in mice, thereby providing strong initial support for our hypothesis that the microbiota is involved in regulation of aggression. Outcomes of this research will lead to a better understanding of the effects of microbiota on behavior in model systems, and open new horizons in recognition of pathways linking microbiota, hormones and aggression
Summary
Aggression is one of the most important social behaviors in nature for procreation and survival. However, understanding the underlying pathways and networks leading to aggression remains a major challenge. Although there has been some progress deciphering genetic factors and neural mechanisms influencing aggression, the precise networks and environmental factors controlling aggression remain a mystery. In this proposal, we suggest the novel concept that host aggression may be regulated in part by the microbiota. We and others have recently linked the gut microbiota, the overall constellation of microorganisms residing within our gut, to behaviors such as risk taking, mating and sexual behavior, as well as hormone production, regulation, and secretion. Here, we aim to characterize the effects of antibiotics, germ-free animal models, and specific microbes on aggression in flies and mice. We further hypothesize that these processes are mediated by pheromones, bacterial and host gene products, and host brain hormones, and will therefore test the involvement of these factors. Considering the microbiota as a novel element regulating aggression is an audacious concept. However, we have demonstrated in a preliminary study that elimination of the gut microbiota significantly raises aggression levels in both D. melanogaster and in mice, thereby providing strong initial support for our hypothesis that the microbiota is involved in regulation of aggression. Outcomes of this research will lead to a better understanding of the effects of microbiota on behavior in model systems, and open new horizons in recognition of pathways linking microbiota, hormones and aggression
Max ERC Funding
1 996 365 €
Duration
Start date: 2021-03-01, End date: 2026-02-28
