Project acronym 3D_Tryps
Project The role of three-dimensional genome architecture in antigenic variation
Researcher (PI) Tim Nicolai SIEGEL
Host Institution (HI) LUDWIG-MAXIMILIANS-UNIVERSITAET MUENCHEN
Call Details Starting Grant (StG), LS6, ERC-2016-STG
Summary Antigenic variation is a widely employed strategy to evade the host immune response. It has similar functional requirements even in evolutionarily divergent pathogens. These include the mutually exclusive expression of antigens and the periodic, nonrandom switching in the expression of different antigens during the course of an infection. Despite decades of research the mechanisms of antigenic variation are not fully understood in any organism.
The recent development of high-throughput sequencing-based assays to probe the 3D genome architecture (Hi-C) has revealed the importance of the spatial organization of DNA inside the nucleus. 3D genome architecture plays a critical role in the regulation of mutually exclusive gene expression and the frequency of translocation between different genomic loci in many eukaryotes. Thus, genome architecture may also be a key regulator of antigenic variation, yet the causal links between genome architecture and the expression of antigens have not been studied systematically. In addition, the development of CRISPR-Cas9-based approaches to perform nucleotide-specific genome editing has opened unprecedented opportunities to study the influence of DNA sequence elements on the spatial organization of DNA and how this impacts antigen expression.
I have adapted both Hi-C and CRISPR-Cas9 technology to the protozoan parasite Trypanosoma brucei, one of the most important model organisms to study antigenic variation. These techniques will enable me to bridge the field of antigenic variation research with that of genome architecture. I will perform the first systematic analysis of the role of genome architecture in the mutually exclusive and hierarchical expression of antigens in any pathogen.
The experiments outlined in this proposal will provide new insight, facilitating a new view of antigenic variation and may eventually help medical intervention in T. brucei and in other pathogens relying on antigenic variation for their survival.
Summary
Antigenic variation is a widely employed strategy to evade the host immune response. It has similar functional requirements even in evolutionarily divergent pathogens. These include the mutually exclusive expression of antigens and the periodic, nonrandom switching in the expression of different antigens during the course of an infection. Despite decades of research the mechanisms of antigenic variation are not fully understood in any organism.
The recent development of high-throughput sequencing-based assays to probe the 3D genome architecture (Hi-C) has revealed the importance of the spatial organization of DNA inside the nucleus. 3D genome architecture plays a critical role in the regulation of mutually exclusive gene expression and the frequency of translocation between different genomic loci in many eukaryotes. Thus, genome architecture may also be a key regulator of antigenic variation, yet the causal links between genome architecture and the expression of antigens have not been studied systematically. In addition, the development of CRISPR-Cas9-based approaches to perform nucleotide-specific genome editing has opened unprecedented opportunities to study the influence of DNA sequence elements on the spatial organization of DNA and how this impacts antigen expression.
I have adapted both Hi-C and CRISPR-Cas9 technology to the protozoan parasite Trypanosoma brucei, one of the most important model organisms to study antigenic variation. These techniques will enable me to bridge the field of antigenic variation research with that of genome architecture. I will perform the first systematic analysis of the role of genome architecture in the mutually exclusive and hierarchical expression of antigens in any pathogen.
The experiments outlined in this proposal will provide new insight, facilitating a new view of antigenic variation and may eventually help medical intervention in T. brucei and in other pathogens relying on antigenic variation for their survival.
Max ERC Funding
1 498 175 €
Duration
Start date: 2017-04-01, End date: 2022-03-31
Project acronym ALLERGUT
Project Mucosal Tolerance and Allergic Predisposition: Does it all start in the gut?
Researcher (PI) Caspar OHNMACHT
Host Institution (HI) HELMHOLTZ ZENTRUM MUENCHEN DEUTSCHES FORSCHUNGSZENTRUM FUER GESUNDHEIT UND UMWELT GMBH
Call Details Starting Grant (StG), LS6, ERC-2016-STG
Summary Currently, more than 30% of all Europeans suffer from one or more allergic disorder but treatment is still mostly symptomatic due to a lack of understanding the underlying causality. Allergies are caused by type 2 immune responses triggered by recognition of harmless antigens. Both genetic and environmental factors have been proposed to favour allergic predisposition and both factors have a huge impact on the symbiotic microbiota and the intestinal immune system. Recently we and others showed that the transcription factor ROR(γt) seems to play a key role in mucosal tolerance in the gut and also regulates intestinal type 2 immune responses.
Based on these results I postulate two major events in the gut for the development of an allergy in the lifetime of an individual: First, a failure to establish mucosal tolerance or anergy constitutes a necessity for the outbreak of allergic symptoms and allergic disease. Second, a certain ‘core’ microbiome or pathway of the intestinal microbiota predispose certain individuals for the later development of allergic disorders. Therefore, I will address the following aims:
1) Influence of ROR(γt) on mucosal tolerance induction and allergic disorders
2) Elucidate the T cell receptor repertoire of intestinal Th2 and ROR(γt)+ Tregs and assess the role of alternative NFκB pathway for induction of mucosal tolerance
3) Identification of ‘core’ microbiome signatures or metabolic pathways that favour allergic predisposition
ALLERGUT will provide ground-breaking knowledge on molecular mechanisms of the failure of mucosal tolerance in the gut and will prove if the resident ROR(γt)+ T(reg) cells can function as a mechanistic starting point for molecular intervention strategies on the background of the hygiene hypothesis. The vision of ALLERGUT is to diagnose mucosal disbalance, prevent and treat allergic disorders even before outbreak and thereby promote Public Health initiative for better living.
Summary
Currently, more than 30% of all Europeans suffer from one or more allergic disorder but treatment is still mostly symptomatic due to a lack of understanding the underlying causality. Allergies are caused by type 2 immune responses triggered by recognition of harmless antigens. Both genetic and environmental factors have been proposed to favour allergic predisposition and both factors have a huge impact on the symbiotic microbiota and the intestinal immune system. Recently we and others showed that the transcription factor ROR(γt) seems to play a key role in mucosal tolerance in the gut and also regulates intestinal type 2 immune responses.
Based on these results I postulate two major events in the gut for the development of an allergy in the lifetime of an individual: First, a failure to establish mucosal tolerance or anergy constitutes a necessity for the outbreak of allergic symptoms and allergic disease. Second, a certain ‘core’ microbiome or pathway of the intestinal microbiota predispose certain individuals for the later development of allergic disorders. Therefore, I will address the following aims:
1) Influence of ROR(γt) on mucosal tolerance induction and allergic disorders
2) Elucidate the T cell receptor repertoire of intestinal Th2 and ROR(γt)+ Tregs and assess the role of alternative NFκB pathway for induction of mucosal tolerance
3) Identification of ‘core’ microbiome signatures or metabolic pathways that favour allergic predisposition
ALLERGUT will provide ground-breaking knowledge on molecular mechanisms of the failure of mucosal tolerance in the gut and will prove if the resident ROR(γt)+ T(reg) cells can function as a mechanistic starting point for molecular intervention strategies on the background of the hygiene hypothesis. The vision of ALLERGUT is to diagnose mucosal disbalance, prevent and treat allergic disorders even before outbreak and thereby promote Public Health initiative for better living.
Max ERC Funding
1 498 175 €
Duration
Start date: 2017-07-01, End date: 2022-06-30
Project acronym Baby DCs
Project Age-dependent Regulation of Dendritic Cell Development and Function
Researcher (PI) Barbara Ursula SCHRAML
Host Institution (HI) LUDWIG-MAXIMILIANS-UNIVERSITAET MUENCHEN
Call Details Starting Grant (StG), LS6, ERC-2016-STG
Summary Early life immune balance is essential for survival and establishment of healthy immunity in later life. We aim to define how age-dependent regulation of dendritic cell (DC) development contributes to this crucial immune balance. DCs are versatile controllers of immunity that in neonates are qualitatively distinct from adults. Why such age-dependent differences exist is unclear but newborn DCs are considered underdeveloped and functionally immature.
Using ontogenetic tracing of conventional DC precursors, I have found a previously unappreciated developmental heterogeneity of DCs that is particularly prominent in young mice. Preliminary data indicate that distinct waves of DC poiesis contribute to the functional differences between neonatal and adult DCs. I hypothesize that the neonatal DC compartment is not immature but rather that DC poiesis is developmentally regulated to create essential age-dependent immune balance. Further, I have identified a unique situation in early life to address a fundamental biological question, namely to what extent cellular function is pre-programmed by developmental origin (nature) versus environmental factors (nurture).
In this proposal, we will first use novel models to fate map the origin of the DC compartment with age. We will then define to what extent cellular origin determines age-dependent functions of DCs in immunity. Using innovative comparative gene expression profiling and integrative epigenomic analysis the cell intrinsic mechanisms regulating the age-dependent functions of DCs will be characterized. Because environmental factors in utero and after birth critically influence immune balance, we will finally define the impact of maternal infection and metabolic disease, as well as early microbial encounter on DC poiesis. Characterizing how developmentally regulated DC poiesis shapes the unique features of early life immunity will provide novel insights into immune development that are vital to advance vaccine strategies.
Summary
Early life immune balance is essential for survival and establishment of healthy immunity in later life. We aim to define how age-dependent regulation of dendritic cell (DC) development contributes to this crucial immune balance. DCs are versatile controllers of immunity that in neonates are qualitatively distinct from adults. Why such age-dependent differences exist is unclear but newborn DCs are considered underdeveloped and functionally immature.
Using ontogenetic tracing of conventional DC precursors, I have found a previously unappreciated developmental heterogeneity of DCs that is particularly prominent in young mice. Preliminary data indicate that distinct waves of DC poiesis contribute to the functional differences between neonatal and adult DCs. I hypothesize that the neonatal DC compartment is not immature but rather that DC poiesis is developmentally regulated to create essential age-dependent immune balance. Further, I have identified a unique situation in early life to address a fundamental biological question, namely to what extent cellular function is pre-programmed by developmental origin (nature) versus environmental factors (nurture).
In this proposal, we will first use novel models to fate map the origin of the DC compartment with age. We will then define to what extent cellular origin determines age-dependent functions of DCs in immunity. Using innovative comparative gene expression profiling and integrative epigenomic analysis the cell intrinsic mechanisms regulating the age-dependent functions of DCs will be characterized. Because environmental factors in utero and after birth critically influence immune balance, we will finally define the impact of maternal infection and metabolic disease, as well as early microbial encounter on DC poiesis. Characterizing how developmentally regulated DC poiesis shapes the unique features of early life immunity will provide novel insights into immune development that are vital to advance vaccine strategies.
Max ERC Funding
1 500 000 €
Duration
Start date: 2017-06-01, End date: 2022-05-31
Project acronym DemandDemoc
Project Demand for Democracy
Researcher (PI) Davide Werner CANTONI
Host Institution (HI) LUDWIG-MAXIMILIANS-UNIVERSITAET MUENCHEN
Call Details Starting Grant (StG), SH1, ERC-2016-STG
Summary Historically, people around the world have demanded democratic institutions. Such democratic movements propel political change and also determine economic outcomes. In this project, we ask, how do political preferences, beliefs, and second-order beliefs shape the strategic decision to participate in a movement demanding democracy? Existing scholarship is unsatisfactory because it is conducted ex post: preferences, beliefs, and behavior have converged to a new equilibrium. In contrast, we examine a democratic movement in real time, studying the ongoing democracy movement in Hong Kong.
Our study is composed of four parts. In Part 1, we collect panel survey data from Hong Kong university students, a particularly politically active subpopulation. We collect data on preferences, behavior, beliefs, and second-order beliefs using incentivized and indirect elicitation to encourage truthful reporting. We analyze the associations among these variables to shed light on the drivers of participation in the democracy movement.
In Part 2, we exploit experimental variation in the provision of information to study political coordination. Among participants in the panel survey, we provide information regarding the preferences and beliefs of other students. We examine whether exposure to information regarding peers causes students to update their beliefs and change their behavior.
In Part 3, we extend the analysis in Part 1 to a nationally representative sample of Hong Kong citizens. To do so, we have added a module regarding political preferences, beliefs, and behavior (including incentivized questions and questions providing cover for responses to politically sensitive topics) to the HKPSSD panel survey.
In Part 4, we study preferences for redistribution – plausibly a central driver for demands for political rights – among Hong Kong citizens and mainland Chinese. We examine how these preferences differ across populations, as well as their link to support for democracy.
Summary
Historically, people around the world have demanded democratic institutions. Such democratic movements propel political change and also determine economic outcomes. In this project, we ask, how do political preferences, beliefs, and second-order beliefs shape the strategic decision to participate in a movement demanding democracy? Existing scholarship is unsatisfactory because it is conducted ex post: preferences, beliefs, and behavior have converged to a new equilibrium. In contrast, we examine a democratic movement in real time, studying the ongoing democracy movement in Hong Kong.
Our study is composed of four parts. In Part 1, we collect panel survey data from Hong Kong university students, a particularly politically active subpopulation. We collect data on preferences, behavior, beliefs, and second-order beliefs using incentivized and indirect elicitation to encourage truthful reporting. We analyze the associations among these variables to shed light on the drivers of participation in the democracy movement.
In Part 2, we exploit experimental variation in the provision of information to study political coordination. Among participants in the panel survey, we provide information regarding the preferences and beliefs of other students. We examine whether exposure to information regarding peers causes students to update their beliefs and change their behavior.
In Part 3, we extend the analysis in Part 1 to a nationally representative sample of Hong Kong citizens. To do so, we have added a module regarding political preferences, beliefs, and behavior (including incentivized questions and questions providing cover for responses to politically sensitive topics) to the HKPSSD panel survey.
In Part 4, we study preferences for redistribution – plausibly a central driver for demands for political rights – among Hong Kong citizens and mainland Chinese. We examine how these preferences differ across populations, as well as their link to support for democracy.
Max ERC Funding
1 494 647 €
Duration
Start date: 2017-03-01, End date: 2022-02-28
Project acronym Diet-namic
Project From fast food to healthy diet: Addressing the dynamic molecular mechanism of sequential diet switch-induced T cell plasticity for the purpose of developing new treatments for immuno-mediated diseases
Researcher (PI) Nicola Gagliani
Host Institution (HI) UNIVERSITAETSKLINIKUM HAMBURG-EPPENDORF
Call Details Starting Grant (StG), LS6, ERC-2016-STG
Summary "The incidence of chronic immune-mediated inflammatory diseases is continually increasing. Chronic inflammation has been linked to intestinal carcinogenesis, which is the second leading cause of cancer-related deaths. The cause of this increase could be the unprecedented dietary abundance typical of “Western” countries. Different types of diets shape the genetic composition and metabolic activity of human intestinal microorganisms; microbiota. There is a continuous cross talk between the microbiota and the immune system. For these reasons, the hypothesis that a “bad” diet promotes a chronic state of intestinal inflammation by shaping the microbiota and in turn carcinogenesis could be supported. However, this hypothesis and whether this is a reversible process remain to be tested.
It has recently been shown that the composition and metabolism of the microbiota is plastic and it can be rapidly “reprogrammed” by switching to a healthier diet. This plastic behaviour has also been attributed to T helper cells. We have shown that Th17 cells, originally thought to be a stable T helper linage, can convert into a more pathogenic phenotype contributing to chronic inflammation or can acquire regulatory functions promoting the resolution of the inflammation.
This project aims to reveal whether mouse and human Th17 cells can quickly adapt to the microbiota as the microbiota does to the diet and in turn mediate the diet effects. By using a unique set of sophisticated transgenic mice we will also test whether the immune system can be corrected by a “simple” change in diet – a widely held belief not yet substantiated.
Studying the potential ""synchronized ballet"" of the diet and the immune system will reveal both the enormous dynamism and the revolutionary therapeutic opportunities intrinsic to T cell biology. This project will furthermore identify molecular targets for pharmacological treatments to reverse inflammatory diseases when a simple diet change no longer suffices."
Summary
"The incidence of chronic immune-mediated inflammatory diseases is continually increasing. Chronic inflammation has been linked to intestinal carcinogenesis, which is the second leading cause of cancer-related deaths. The cause of this increase could be the unprecedented dietary abundance typical of “Western” countries. Different types of diets shape the genetic composition and metabolic activity of human intestinal microorganisms; microbiota. There is a continuous cross talk between the microbiota and the immune system. For these reasons, the hypothesis that a “bad” diet promotes a chronic state of intestinal inflammation by shaping the microbiota and in turn carcinogenesis could be supported. However, this hypothesis and whether this is a reversible process remain to be tested.
It has recently been shown that the composition and metabolism of the microbiota is plastic and it can be rapidly “reprogrammed” by switching to a healthier diet. This plastic behaviour has also been attributed to T helper cells. We have shown that Th17 cells, originally thought to be a stable T helper linage, can convert into a more pathogenic phenotype contributing to chronic inflammation or can acquire regulatory functions promoting the resolution of the inflammation.
This project aims to reveal whether mouse and human Th17 cells can quickly adapt to the microbiota as the microbiota does to the diet and in turn mediate the diet effects. By using a unique set of sophisticated transgenic mice we will also test whether the immune system can be corrected by a “simple” change in diet – a widely held belief not yet substantiated.
Studying the potential ""synchronized ballet"" of the diet and the immune system will reveal both the enormous dynamism and the revolutionary therapeutic opportunities intrinsic to T cell biology. This project will furthermore identify molecular targets for pharmacological treatments to reverse inflammatory diseases when a simple diet change no longer suffices."
Max ERC Funding
1 499 695 €
Duration
Start date: 2016-12-01, End date: 2021-11-30
Project acronym ImmProDynamics
Project Dissecting the interplay between the dynamics of immune responses and pathogen proliferation in vivo
Researcher (PI) Andreas J. Müller
Host Institution (HI) OTTO-VON-GUERICKE-UNIVERSITAET MAGDEBURG
Call Details Starting Grant (StG), LS6, ERC-2016-STG
Summary Pathogen proliferation has profound implications for its persistence, treatment strategies, and the induction and execution of protective immune responses. In vivo, pathogen proliferation rates are heterogenic, confronting the immune system with a variety of microbial physiological states. It is unknown if, and by what molecular mechanism, the immune response can distinguish these different states on a cellular level. Also, understanding the link between pathogen proliferation and immune cell dynamics could provide critical information on how infections can be controlled, and how to counteract pathogen persistence and antibiotic resistance. However, this question has never been addressed due to difficulties in studying the dynamics of immune cells and at the same time probing pathogen proliferation.
In this project, we will make use of a novel in vivo reporter system that I have developed, in order to determine the role of the pathogen's proliferation for its interaction with the immune system. Specifically, we will (1) determine the tissue niche in which the pathogen proliferates, (2) investigate the differential dynamics of phagocyte-pathogen- and of T cell-APC-interactions related to pathogen proliferation rate, (3) manipulate the relationship between pathogen proliferation and immune cell dynamics by using proliferation-deficient mutants and optogenetic pathogen inactivation, (4) identify signaling pathways that are differentially induced in cells infected by high versus low proliferating pathogens, and test their involvement in differential immune cell dynamics related to pathogen proliferation.
ImmProDynamics will for the first time provide insights into how cells of the immune system react to distinct pathogen proliferative states in vivo. This will greatly expand our knowledge of host-pathogen interactions, which will be critical for the design of efficient vaccines and antimicrobial therapy.
Summary
Pathogen proliferation has profound implications for its persistence, treatment strategies, and the induction and execution of protective immune responses. In vivo, pathogen proliferation rates are heterogenic, confronting the immune system with a variety of microbial physiological states. It is unknown if, and by what molecular mechanism, the immune response can distinguish these different states on a cellular level. Also, understanding the link between pathogen proliferation and immune cell dynamics could provide critical information on how infections can be controlled, and how to counteract pathogen persistence and antibiotic resistance. However, this question has never been addressed due to difficulties in studying the dynamics of immune cells and at the same time probing pathogen proliferation.
In this project, we will make use of a novel in vivo reporter system that I have developed, in order to determine the role of the pathogen's proliferation for its interaction with the immune system. Specifically, we will (1) determine the tissue niche in which the pathogen proliferates, (2) investigate the differential dynamics of phagocyte-pathogen- and of T cell-APC-interactions related to pathogen proliferation rate, (3) manipulate the relationship between pathogen proliferation and immune cell dynamics by using proliferation-deficient mutants and optogenetic pathogen inactivation, (4) identify signaling pathways that are differentially induced in cells infected by high versus low proliferating pathogens, and test their involvement in differential immune cell dynamics related to pathogen proliferation.
ImmProDynamics will for the first time provide insights into how cells of the immune system react to distinct pathogen proliferative states in vivo. This will greatly expand our knowledge of host-pathogen interactions, which will be critical for the design of efficient vaccines and antimicrobial therapy.
Max ERC Funding
1 499 525 €
Duration
Start date: 2017-03-01, End date: 2022-02-28
Project acronym IMMUNE CELL SWARMS
Project Innate Immune Cell Swarms: Integrating and Adapting Single Cell and Population Dynamics in Inflamed and Infected Tissues
Researcher (PI) Tim LÄMMERMANN
Host Institution (HI) MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV
Call Details Starting Grant (StG), LS6, ERC-2016-STG
Summary Neutrophils are essential effector cells of the innate immune response. Intravital microscopy studies have recently changed our perspective on neutrophil tissue dynamics. They revealed swarm-like migration patterns in several models of inflammation and infection: Neutrophil populations show strikingly coordinated behavior with phases of highly directed chemotaxis and clustering at local sites of tissue damage. My previous work established that neutrophils self-amplify this swarming response by auto-signaling, which provided the first molecular basis for the collective nature of neutrophil swarms (Lämmermann et al., Nature 2013). However, we are still at the beginning of unraveling the molecular pathways behind this newly discovered phenomenon.
Most importantly, we completely lack insight into the signals and mechanisms that stop neutrophil swarms in the resolution phase of an immune response. Since excess neutrophil accumulations cause deleterious tissue destruction in many inflammatory diseases, novel insights into the mechanisms, which prevent extensive swarm aggregation, might be of considerable therapeutic value. In accord with this, our proposal follows three aims: (i) dissecting the cellular and molecular mechanisms that control the resolution phase of neutrophil swarming, (ii) establishing a conceptual framework of how swarming immune cells adapt their dynamics to changing inflammatory milieus, and (iii) developing an integrated view on how neutrophil swarms are controlled by secondary waves of myeloid cell swarms. To achieve our goals, we will combine targeted mouse genetics with live cell imaging of immune cell dynamics in living tissues and the use of innovative mimics of physiological environments.
Our future findings on innate immune cell swarms promise to (i) advance our knowledge on leukocyte navigation in complex inflammatory tissues and (ii) provide new avenues for the therapeutic modulation of tissue regeneration after inflammation and infection.
Summary
Neutrophils are essential effector cells of the innate immune response. Intravital microscopy studies have recently changed our perspective on neutrophil tissue dynamics. They revealed swarm-like migration patterns in several models of inflammation and infection: Neutrophil populations show strikingly coordinated behavior with phases of highly directed chemotaxis and clustering at local sites of tissue damage. My previous work established that neutrophils self-amplify this swarming response by auto-signaling, which provided the first molecular basis for the collective nature of neutrophil swarms (Lämmermann et al., Nature 2013). However, we are still at the beginning of unraveling the molecular pathways behind this newly discovered phenomenon.
Most importantly, we completely lack insight into the signals and mechanisms that stop neutrophil swarms in the resolution phase of an immune response. Since excess neutrophil accumulations cause deleterious tissue destruction in many inflammatory diseases, novel insights into the mechanisms, which prevent extensive swarm aggregation, might be of considerable therapeutic value. In accord with this, our proposal follows three aims: (i) dissecting the cellular and molecular mechanisms that control the resolution phase of neutrophil swarming, (ii) establishing a conceptual framework of how swarming immune cells adapt their dynamics to changing inflammatory milieus, and (iii) developing an integrated view on how neutrophil swarms are controlled by secondary waves of myeloid cell swarms. To achieve our goals, we will combine targeted mouse genetics with live cell imaging of immune cell dynamics in living tissues and the use of innovative mimics of physiological environments.
Our future findings on innate immune cell swarms promise to (i) advance our knowledge on leukocyte navigation in complex inflammatory tissues and (ii) provide new avenues for the therapeutic modulation of tissue regeneration after inflammation and infection.
Max ERC Funding
1 500 000 €
Duration
Start date: 2017-02-01, End date: 2022-01-31
Project acronym OPTRASTOCH
Project Optimal Transport and Stochastic Dynamics
Researcher (PI) Jan Maas
Host Institution (HI) INSTITUTE OF SCIENCE AND TECHNOLOGYAUSTRIA
Call Details Starting Grant (StG), PE1, ERC-2016-STG
Summary Many important properties of stochastic processes are deeply connected with the underlying geometric structure. The crucial quantity in many applications is a lower bound on the Ricci curvature, which yields powerful applications to concentration of measure, isoperimetry, and convergence to equilibrium.
Since many important processes are defined in discrete, infinite-dimensional, or singular spaces, major research activity has been devoted to developing a theory of Ricci curvature beyond the classical
Riemannian setting. This led to the powerful theories of Bakry-Émery and Lott-Sturm-Villani, which have been extremely successful in the analysis of geodesic spaces and diffusion processes. Building on our recent work, we will develop a wide research program that allows us to significantly enlarge the scope of these ideas.
A) Firstly, we develop a comprehensive theory of curvature-dimension for discrete spaces based on geodesic convexity of entropy functionals along discrete optimal transport. Promising first results suggest that the theory initiated by the PI provides the appropriate framework for obtaining many powerful results from geometric analysis in the discrete setting.
B) Secondly, we analyse discrete stochastic dynamics using methods from optimal transport.
We focus on non-reversible Markov processes, which requires a significant extension of the existing gradient flow theory, and develop new methods for proving convergence of discrete stochastic dynamics.
C) Thirdly, we develop an optimal transport approach to the analysis of quantum Markov processes. We will perform a thorough investigation of noncommutative optimal transport, we aim for geometric and functional inequalities in quantum probability, and apply the results to the analysis
of quantum Markov processes.
The project extends the scope of optimal transport methods significantly and makes a fundamental contribution to the conceptual understanding of discrete curvature.
Summary
Many important properties of stochastic processes are deeply connected with the underlying geometric structure. The crucial quantity in many applications is a lower bound on the Ricci curvature, which yields powerful applications to concentration of measure, isoperimetry, and convergence to equilibrium.
Since many important processes are defined in discrete, infinite-dimensional, or singular spaces, major research activity has been devoted to developing a theory of Ricci curvature beyond the classical
Riemannian setting. This led to the powerful theories of Bakry-Émery and Lott-Sturm-Villani, which have been extremely successful in the analysis of geodesic spaces and diffusion processes. Building on our recent work, we will develop a wide research program that allows us to significantly enlarge the scope of these ideas.
A) Firstly, we develop a comprehensive theory of curvature-dimension for discrete spaces based on geodesic convexity of entropy functionals along discrete optimal transport. Promising first results suggest that the theory initiated by the PI provides the appropriate framework for obtaining many powerful results from geometric analysis in the discrete setting.
B) Secondly, we analyse discrete stochastic dynamics using methods from optimal transport.
We focus on non-reversible Markov processes, which requires a significant extension of the existing gradient flow theory, and develop new methods for proving convergence of discrete stochastic dynamics.
C) Thirdly, we develop an optimal transport approach to the analysis of quantum Markov processes. We will perform a thorough investigation of noncommutative optimal transport, we aim for geometric and functional inequalities in quantum probability, and apply the results to the analysis
of quantum Markov processes.
The project extends the scope of optimal transport methods significantly and makes a fundamental contribution to the conceptual understanding of discrete curvature.
Max ERC Funding
1 074 590 €
Duration
Start date: 2017-02-01, End date: 2022-01-31
Project acronym Plat-IL-1
Project Pathophysiology of platelet-derived Interleukin 1
Researcher (PI) BERNARDO SIMOES FRANKLIN
Host Institution (HI) UNIVERSITAETSKLINIKUM BONN
Call Details Starting Grant (StG), LS6, ERC-2016-STG
Summary The Interleukin (IL)-1 family of pro-inflammatory cytokines are among the most potent pyrogens, and their excessive production can cause several auto-inflammatory syndromes. Additionally, overabundance of IL-1 cytokines can trigger, or contribute to a range of inflammatory and metabolic disorders. The expression of the key members of the IL-1 family, such as IL-1β and IL-18, is regulated at both the transcriptional and post-transcriptional levels. IL-1β and IL-18, are produced as inactive precursors, which require activation of caspase-1 by the inflammasomes for their maturation and release by from cells, occasionally at the cost of caspase-1 mediated-cell death. We have recently discovered that inflammasomes are released into the extracellular space where they remain active after the demise of activated cells, and that extracellular inflammasomes can amplify inflammation by sustaining extracellular production of IL-1β. However, the sources of extracellular pro-IL-1β are not known. Recent advances in platelet proteomics have revealed that these non-nucleated cells are able to produce their own cytokines, including soluble IL-1β and membrane-bound IL-1α, and are able to significantly magnify IL-1 production by immune cells. As platelets outnumber leukocytes by several folds, they could potentially be the major source of extracellular inflammasomes in the body, or be a major producer of IL-1 precursors that are cleaved by extracellular inflammasomes released from dying immune cells. In this proposal, we will investigate the mechanism(s) by which platelets produce IL-1, and the specific contribution of platelet-derived IL-1 to sterile inflammation, or host resistance to bacterial and viral infection. We believe that a deeper understanding of platelet-IL-1 and their interaction with immune cells during sterile inflammation, or infection might help to uncover new targets for immune-therapies.
Summary
The Interleukin (IL)-1 family of pro-inflammatory cytokines are among the most potent pyrogens, and their excessive production can cause several auto-inflammatory syndromes. Additionally, overabundance of IL-1 cytokines can trigger, or contribute to a range of inflammatory and metabolic disorders. The expression of the key members of the IL-1 family, such as IL-1β and IL-18, is regulated at both the transcriptional and post-transcriptional levels. IL-1β and IL-18, are produced as inactive precursors, which require activation of caspase-1 by the inflammasomes for their maturation and release by from cells, occasionally at the cost of caspase-1 mediated-cell death. We have recently discovered that inflammasomes are released into the extracellular space where they remain active after the demise of activated cells, and that extracellular inflammasomes can amplify inflammation by sustaining extracellular production of IL-1β. However, the sources of extracellular pro-IL-1β are not known. Recent advances in platelet proteomics have revealed that these non-nucleated cells are able to produce their own cytokines, including soluble IL-1β and membrane-bound IL-1α, and are able to significantly magnify IL-1 production by immune cells. As platelets outnumber leukocytes by several folds, they could potentially be the major source of extracellular inflammasomes in the body, or be a major producer of IL-1 precursors that are cleaved by extracellular inflammasomes released from dying immune cells. In this proposal, we will investigate the mechanism(s) by which platelets produce IL-1, and the specific contribution of platelet-derived IL-1 to sterile inflammation, or host resistance to bacterial and viral infection. We believe that a deeper understanding of platelet-IL-1 and their interaction with immune cells during sterile inflammation, or infection might help to uncover new targets for immune-therapies.
Max ERC Funding
1 488 854 €
Duration
Start date: 2017-03-01, End date: 2022-02-28
