Project acronym APOSITE
Project Apoptotic foci: composition, structure and dynamics
Researcher (PI) Ana GARCIA SAEZ
Host Institution (HI) EBERHARD KARLS UNIVERSITAET TUEBINGEN
Call Details Consolidator Grant (CoG), LS3, ERC-2018-COG
Summary Apoptotic cell death is essential for development, immune function or tissue homeostasis, and it is often deregulated in disease. Mitochondrial outer membrane permeabilization (MOMP) is central for apoptosis execution and plays a key role in its inflammatory outcome. Knowing the architecture of the macromolecular machineries mediating MOMP is crucial for understanding their function and for the clinical use of apoptosis.
Our recent work reveals that Bax and Bak dimers form distinct line, arc and ring assemblies at specific apoptotic foci to mediate MOMP. However, the molecular structure and mechanisms controlling the spatiotemporal formation and range of action of the apoptotic foci are missing. To address this fundamental gap in our knowledge, we aim to unravel the composition, dynamics and structure of apoptotic foci and to understand how they are integrated to orchestrate function. We will reach this goal by building on our expertise in cell death and cutting-edge imaging and by developing a new analytical pipeline to:
1) Identify the composition of apoptotic foci using in situ proximity-dependent labeling and extraction of near-native Bax/Bak membrane complexes coupled to mass spectrometry.
2) Define their contribution to apoptosis and its immunogenicity and establish their assembly dynamics to correlate it with apoptosis progression by live cell imaging.
3) Determine the stoichiometry and structural organization of the apoptotic foci by combining single molecule fluorescence and advanced electron microscopies.
This multidisciplinary approach offers high chances to solve the long-standing question of how Bax and Bak mediate MOMP. APOSITE will provide textbook knowledge of the mitochondrial contribution to cell death and inflammation. The implementation of this new analytical framework will open novel research avenues in membrane and organelle biology. Ultimately, understanding of Bax and Bak structure/function will help develop apoptosis modulators for medicine.
Summary
Apoptotic cell death is essential for development, immune function or tissue homeostasis, and it is often deregulated in disease. Mitochondrial outer membrane permeabilization (MOMP) is central for apoptosis execution and plays a key role in its inflammatory outcome. Knowing the architecture of the macromolecular machineries mediating MOMP is crucial for understanding their function and for the clinical use of apoptosis.
Our recent work reveals that Bax and Bak dimers form distinct line, arc and ring assemblies at specific apoptotic foci to mediate MOMP. However, the molecular structure and mechanisms controlling the spatiotemporal formation and range of action of the apoptotic foci are missing. To address this fundamental gap in our knowledge, we aim to unravel the composition, dynamics and structure of apoptotic foci and to understand how they are integrated to orchestrate function. We will reach this goal by building on our expertise in cell death and cutting-edge imaging and by developing a new analytical pipeline to:
1) Identify the composition of apoptotic foci using in situ proximity-dependent labeling and extraction of near-native Bax/Bak membrane complexes coupled to mass spectrometry.
2) Define their contribution to apoptosis and its immunogenicity and establish their assembly dynamics to correlate it with apoptosis progression by live cell imaging.
3) Determine the stoichiometry and structural organization of the apoptotic foci by combining single molecule fluorescence and advanced electron microscopies.
This multidisciplinary approach offers high chances to solve the long-standing question of how Bax and Bak mediate MOMP. APOSITE will provide textbook knowledge of the mitochondrial contribution to cell death and inflammation. The implementation of this new analytical framework will open novel research avenues in membrane and organelle biology. Ultimately, understanding of Bax and Bak structure/function will help develop apoptosis modulators for medicine.
Max ERC Funding
2 000 000 €
Duration
Start date: 2019-04-01, End date: 2024-03-31
Project acronym AutoCPS
Project Automated Synthesis of Cyber-Physical Systems: A Compositional Approach
Researcher (PI) Majid ZAMANI
Host Institution (HI) LUDWIG-MAXIMILIANS-UNIVERSITAET MUENCHEN
Call Details Starting Grant (StG), PE7, ERC-2018-STG
Summary Embedded Control software plays a critical role in many safety-critical applications. For instance, modern vehicles use interacting software and hardware components to control steering and braking. Control software forms the main core of autonomous transportation, power networks, and aerospace. These applications are examples of cyber-physical systems (CPS), where distributed software systems interact tightly with spatially distributed physical systems with complex dynamics. CPS are becoming ubiquitous due to rapid advances in computation, communication, and memory. However, the development of core control software running in these systems is still ad hoc and error-prone and much of the engineering costs today go into ensuring that control software works correctly.
In order to reduce the design costs and guaranteeing its correctness, I aim to develop an innovative design process, in which the embedded control software is synthesized from high-level correctness requirements in a push-button and formal manner. Requirements for modern CPS applications go beyond conventional properties in control theory (e.g. stability) and in computer science (e.g. protocol design). Here, I propose a compositional methodology for automated synthesis of control software by combining compositional techniques from computer science (e.g. assume-guarantee rules) with those from control theory (e.g. small-gain theorems). I will leverage decomposition and abstraction as two key tools to tackle the design complexity, by either breaking the design object into semi-independent parts or by aggregating components and eliminating unnecessary details. My project is high-risk because it requires a fundamental re-thinking of design techniques till now studied in separate disciplines. It is high-gain because a successful method for automated synthesis of control software will make it finally possible to develop complex yet reliable CPS applications while considerably reducing the engineering cost.
Summary
Embedded Control software plays a critical role in many safety-critical applications. For instance, modern vehicles use interacting software and hardware components to control steering and braking. Control software forms the main core of autonomous transportation, power networks, and aerospace. These applications are examples of cyber-physical systems (CPS), where distributed software systems interact tightly with spatially distributed physical systems with complex dynamics. CPS are becoming ubiquitous due to rapid advances in computation, communication, and memory. However, the development of core control software running in these systems is still ad hoc and error-prone and much of the engineering costs today go into ensuring that control software works correctly.
In order to reduce the design costs and guaranteeing its correctness, I aim to develop an innovative design process, in which the embedded control software is synthesized from high-level correctness requirements in a push-button and formal manner. Requirements for modern CPS applications go beyond conventional properties in control theory (e.g. stability) and in computer science (e.g. protocol design). Here, I propose a compositional methodology for automated synthesis of control software by combining compositional techniques from computer science (e.g. assume-guarantee rules) with those from control theory (e.g. small-gain theorems). I will leverage decomposition and abstraction as two key tools to tackle the design complexity, by either breaking the design object into semi-independent parts or by aggregating components and eliminating unnecessary details. My project is high-risk because it requires a fundamental re-thinking of design techniques till now studied in separate disciplines. It is high-gain because a successful method for automated synthesis of control software will make it finally possible to develop complex yet reliable CPS applications while considerably reducing the engineering cost.
Max ERC Funding
1 470 800 €
Duration
Start date: 2019-02-01, End date: 2024-01-31
Project acronym BRAIN-MATCH
Project Matching CNS Lineage Maps with Molecular Brain Tumor Portraits for Translational Exploitation
Researcher (PI) Stefan PFISTER
Host Institution (HI) DEUTSCHES KREBSFORSCHUNGSZENTRUM HEIDELBERG
Call Details Consolidator Grant (CoG), LS2, ERC-2018-COG
Summary Brain tumors represent an extremely heterogeneous group of more than 100 different molecularly distinct diseases, many of which are still almost uniformly lethal despite five decades of clinical trials. In contrast to hematologic malignancies and carcinomas, the cell-of-origin for the vast majority of these entities is unknown. This knowledge gap currently precludes a comprehensive understanding of tumor biology and also limits translational exploitation (e.g., utilizing lineage targets for novel therapies and circulating brain tumor cells for liquid biopsies).
The BRAIN-MATCH project represents an ambitious program to address this challenge and unmet medical need by taking an approach that (i) extensively utilizes existing molecular profiles of more than 30,000 brain tumor samples covering more than 100 different entities, publicly available single-cell sequencing data of normal brain regions, and bulk normal tissue data at different times of development across different species; (ii) generates unprecedented maps of normal human CNS development by using state-of-the art novel technologies; (iii) matches these molecular portraits of normal cell types with tumor datasets in order to identify specific cell-of-origin populations for individual tumor entities; and (iv) validates the most promising cell-of-origin populations and tumor-specific lineage and/or surface markers in vivo.
The expected outputs of BRAIN-MATCH are four-fold: (i) delivery of an unprecedented atlas of human normal CNS development, which will also be of great relevance for diverse fields other than cancer; (ii) functional validation of at least three lineage targets; (iii) isolation and molecular characterization of circulating brain tumor cells from patients´ blood for at least five tumor entities; and (iv) generation of at least three novel mouse models of brain tumor entities for which currently no faithful models exist.
Summary
Brain tumors represent an extremely heterogeneous group of more than 100 different molecularly distinct diseases, many of which are still almost uniformly lethal despite five decades of clinical trials. In contrast to hematologic malignancies and carcinomas, the cell-of-origin for the vast majority of these entities is unknown. This knowledge gap currently precludes a comprehensive understanding of tumor biology and also limits translational exploitation (e.g., utilizing lineage targets for novel therapies and circulating brain tumor cells for liquid biopsies).
The BRAIN-MATCH project represents an ambitious program to address this challenge and unmet medical need by taking an approach that (i) extensively utilizes existing molecular profiles of more than 30,000 brain tumor samples covering more than 100 different entities, publicly available single-cell sequencing data of normal brain regions, and bulk normal tissue data at different times of development across different species; (ii) generates unprecedented maps of normal human CNS development by using state-of-the art novel technologies; (iii) matches these molecular portraits of normal cell types with tumor datasets in order to identify specific cell-of-origin populations for individual tumor entities; and (iv) validates the most promising cell-of-origin populations and tumor-specific lineage and/or surface markers in vivo.
The expected outputs of BRAIN-MATCH are four-fold: (i) delivery of an unprecedented atlas of human normal CNS development, which will also be of great relevance for diverse fields other than cancer; (ii) functional validation of at least three lineage targets; (iii) isolation and molecular characterization of circulating brain tumor cells from patients´ blood for at least five tumor entities; and (iv) generation of at least three novel mouse models of brain tumor entities for which currently no faithful models exist.
Max ERC Funding
1 999 875 €
Duration
Start date: 2019-05-01, End date: 2024-04-30
Project acronym CaLA
Project The Capillary Lock Actuator: A novel bistable microfluidic actuator for cost-effective high-density actuator arrays suitable for large-scale graphical tactile displays
Researcher (PI) Bastian Rapp
Host Institution (HI) ALBERT-LUDWIGS-UNIVERSITAET FREIBURG
Call Details Consolidator Grant (CoG), PE7, ERC-2018-COG
Summary According to the World Health Organization more than 285 million people worldwide are visually impaired. In a world where graphics and online content (images, webpages) become increasingly important the inability to perceive information visually is the primary inhibitor for inclusion. In contrast to display technology for sighted people, tactile displays which translate text and graphics to touchable pixels (taxels) have seen little progress in recent decades. So-called Braille lines which display only a single line of text are still the norm. The reason why graphical tactile displays do not exist is the lack of a suitable actuator technology which allows generating massively parallelized individually addressable cost-effective taxel arrays.
This ERC Consolidator project aims at a revolution in microactuator array technology with a fundamentally new concept termed the Capillary Lock Actuator (CaLA). CaLA is a novel bistable massively parallelizable microfluidic microactuator which overcomes many of the limitations currently associated with microactuators. It can be operated with low-voltage control signals and requires virtually no power for actuation. CaLA harnesses three concepts inherent to microfluidics: positive capillary pressure, segmented flow and controllable locally confined changes in wetting. The project will use CaLA actuator arrays for setting up the very first portable tactile graphic display with 30.000 individually addressable taxels thereby significantly outperforming the state-of-the-art. It will be based on manufacturing techniques for highly complex microstructures in glass invented by my group.
CaLA will be a significant breakthrough in actuator technology and enabling for many applications in microsystem technology. Most importantly, it will be a significant step towards making the information technology inclusive for the visually impaired by providing the first robust cost-effective solution to large-scale tactile displays.
Summary
According to the World Health Organization more than 285 million people worldwide are visually impaired. In a world where graphics and online content (images, webpages) become increasingly important the inability to perceive information visually is the primary inhibitor for inclusion. In contrast to display technology for sighted people, tactile displays which translate text and graphics to touchable pixels (taxels) have seen little progress in recent decades. So-called Braille lines which display only a single line of text are still the norm. The reason why graphical tactile displays do not exist is the lack of a suitable actuator technology which allows generating massively parallelized individually addressable cost-effective taxel arrays.
This ERC Consolidator project aims at a revolution in microactuator array technology with a fundamentally new concept termed the Capillary Lock Actuator (CaLA). CaLA is a novel bistable massively parallelizable microfluidic microactuator which overcomes many of the limitations currently associated with microactuators. It can be operated with low-voltage control signals and requires virtually no power for actuation. CaLA harnesses three concepts inherent to microfluidics: positive capillary pressure, segmented flow and controllable locally confined changes in wetting. The project will use CaLA actuator arrays for setting up the very first portable tactile graphic display with 30.000 individually addressable taxels thereby significantly outperforming the state-of-the-art. It will be based on manufacturing techniques for highly complex microstructures in glass invented by my group.
CaLA will be a significant breakthrough in actuator technology and enabling for many applications in microsystem technology. Most importantly, it will be a significant step towards making the information technology inclusive for the visually impaired by providing the first robust cost-effective solution to large-scale tactile displays.
Max ERC Funding
1 999 750 €
Duration
Start date: 2019-05-01, End date: 2024-04-30
Project acronym CANCERBIOME
Project Cancerbiome: Characterization of the cancer-associated microbiome
Researcher (PI) Peer Bork
Host Institution (HI) EUROPEAN MOLECULAR BIOLOGY LABORATORY
Call Details Advanced Grant (AdG), LS2, ERC-2010-AdG_20100317
Summary Deep environmental sequencing (metagenomics) will be used to characterize microbial communities associated with 3 different cancer types: cervical cancer, oral squamous cell carcinoma and colorectal cancer. For all 3 types, non-invasive molecular diagnostics and prognostics are feasible via utilization of vaginal, oral and faecal samples, respectively. The project consequently aims to identify microbial markers in these ¿readouts¿ that correlate with cancer presence or progression. Microbial markers can be individual species or specific community compositions, but also particular genes or pathways. The microbial communities will be sampled locally at tumor surfaces and in healthy control tissues. After DNA extraction and sequencing, a complex bioinformatics pipeline will be developed to characterise the microbiomes and to identify the cancer-specific functional and phylogenetic markers therein. For colorectal cancer, the project intends to go into more details in that it tries i) to establish a correlation of microbiota with cancer progression and it ii) explores differences between distinct cancer subtypes. For each of the 3 cancer types, at least two samples from 40 individuals will be sequenced (as well as controls) at a depth of at least 5Gb each using Illumina technology. This is expected to be sufficient for the identification of microbial markers and also allows superficial genotyping of the individuals at ca 2-3x coverage as a by-product (the samples will contain considerable amounts of human DNA). Further analyses will be designed to study the potential of certain microbial species or community compositions to enhance or even cause one or more of the 3 cancers. The discovery of such causations will open up research towards directed antimicrobial treatment.
Summary
Deep environmental sequencing (metagenomics) will be used to characterize microbial communities associated with 3 different cancer types: cervical cancer, oral squamous cell carcinoma and colorectal cancer. For all 3 types, non-invasive molecular diagnostics and prognostics are feasible via utilization of vaginal, oral and faecal samples, respectively. The project consequently aims to identify microbial markers in these ¿readouts¿ that correlate with cancer presence or progression. Microbial markers can be individual species or specific community compositions, but also particular genes or pathways. The microbial communities will be sampled locally at tumor surfaces and in healthy control tissues. After DNA extraction and sequencing, a complex bioinformatics pipeline will be developed to characterise the microbiomes and to identify the cancer-specific functional and phylogenetic markers therein. For colorectal cancer, the project intends to go into more details in that it tries i) to establish a correlation of microbiota with cancer progression and it ii) explores differences between distinct cancer subtypes. For each of the 3 cancer types, at least two samples from 40 individuals will be sequenced (as well as controls) at a depth of at least 5Gb each using Illumina technology. This is expected to be sufficient for the identification of microbial markers and also allows superficial genotyping of the individuals at ca 2-3x coverage as a by-product (the samples will contain considerable amounts of human DNA). Further analyses will be designed to study the potential of certain microbial species or community compositions to enhance or even cause one or more of the 3 cancers. The discovery of such causations will open up research towards directed antimicrobial treatment.
Max ERC Funding
2 233 740 €
Duration
Start date: 2011-07-01, End date: 2016-06-30
Project acronym CAPSEVO
Project Evolution of flower morphology: the selfing syndrome in Capsella
Researcher (PI) Michael Lenhard
Host Institution (HI) UNIVERSITAET POTSDAM
Call Details Starting Grant (StG), LS3, ERC-2010-StG_20091118
Summary The change from reproduction by outbreeding to selfing is one of the most frequent evolutionary transitions in plants. This transition is generally accompanied by changes in flower morphology and function, termed the selfing syndrome, including a reduction in flower size and a more closed flower structure. While the loss of self-incompatibility is relatively well understood, little is known about the molecular basis of the associated morphological changes and their evolutionary history. We will address these problems using the species pair Capsella grandiflora (the ancestral outbreeder) and C. rubella (the derived selfing species) as a genetically tractable model. We have established recombinant inbred lines from a cross of C. grandiflora x C. rubella and mapped quantitative trait loci affecting flower size and flower opening. Using this resource, the proposal will address four objectives. (1) We will isolate causal genes underlying the variation in flower size and opening, by combining genetic mapping with next-generation sequencing. (2) We will characterize the developmental and molecular functions of the isolated genes in Capsella and Arabidopsis. (3) We will dissect the molecular basis of the different allelic effects of the causal genes to determine which kinds of mutations have led to the morphological changes. (4) Based on population-genetic analyses of the isolated genes, the evolutionary history of the morphological changes will be retraced. Together, these strands of investigation will provide a detailed understanding of general processes underlying morphological evolution in plants.
Summary
The change from reproduction by outbreeding to selfing is one of the most frequent evolutionary transitions in plants. This transition is generally accompanied by changes in flower morphology and function, termed the selfing syndrome, including a reduction in flower size and a more closed flower structure. While the loss of self-incompatibility is relatively well understood, little is known about the molecular basis of the associated morphological changes and their evolutionary history. We will address these problems using the species pair Capsella grandiflora (the ancestral outbreeder) and C. rubella (the derived selfing species) as a genetically tractable model. We have established recombinant inbred lines from a cross of C. grandiflora x C. rubella and mapped quantitative trait loci affecting flower size and flower opening. Using this resource, the proposal will address four objectives. (1) We will isolate causal genes underlying the variation in flower size and opening, by combining genetic mapping with next-generation sequencing. (2) We will characterize the developmental and molecular functions of the isolated genes in Capsella and Arabidopsis. (3) We will dissect the molecular basis of the different allelic effects of the causal genes to determine which kinds of mutations have led to the morphological changes. (4) Based on population-genetic analyses of the isolated genes, the evolutionary history of the morphological changes will be retraced. Together, these strands of investigation will provide a detailed understanding of general processes underlying morphological evolution in plants.
Max ERC Funding
1 480 826 €
Duration
Start date: 2010-12-01, End date: 2016-11-30
Project acronym CELLMIG
Project Molecular and Cellular Mechanisms Promoting Single-Cell Migration in vivo
Researcher (PI) Erez Raz
Host Institution (HI) WESTFAELISCHE WILHELMS-UNIVERSITAET MUENSTER
Call Details Advanced Grant (AdG), LS3, ERC-2010-AdG_20100317
Summary The regulation of cell migration is central in pattern formation, homeostasis and disease. The proposed research is aimed at investigating the molecular basis for cell motility and the associated polarization of the cell. In view of the dynamic nature of these processes, we have chosen to utilize the migration of Primoridal Germ Cells (PGCs) in zebrafish - a model that offers unique experimental advantages for imaging and experimental manipulations. The fact that molecules facilitating the motility of zebrafish PGCs are evolutionary conserved and the finding that the cells are directed by chemokines, molecules that control a wide range of cell trafficking events in vertebrates, make this in vivo study of particular importance.
The proposed work involves both the functional analysis of previously identified candidates and the identification of molecules, which have a presently unknown effect on the migration process. For both objectives, we will employ novel experimental schemes. We will examine the role of proteins in achieving functional cell polarity compatible with efficient motility and response to directional cues, using unique techniques and analysis tools in the context of the living organism. The precise function of the identified proteins will be determined by combining mathematical tools aimed at quantitatively gauging the role of the molecules in conferring proper cell shape, biophysical methods aimed at measuring forces, rigidity and cytoplasm flow and determination of the effect on the organization of relevant structures using cryo electron tomography.
Together, this approach would provide a non-conventional understanding of cell migration by correlating structural, morphological and dynamic cellular properties with the ability of cells to effectively migrate towards their target.
Summary
The regulation of cell migration is central in pattern formation, homeostasis and disease. The proposed research is aimed at investigating the molecular basis for cell motility and the associated polarization of the cell. In view of the dynamic nature of these processes, we have chosen to utilize the migration of Primoridal Germ Cells (PGCs) in zebrafish - a model that offers unique experimental advantages for imaging and experimental manipulations. The fact that molecules facilitating the motility of zebrafish PGCs are evolutionary conserved and the finding that the cells are directed by chemokines, molecules that control a wide range of cell trafficking events in vertebrates, make this in vivo study of particular importance.
The proposed work involves both the functional analysis of previously identified candidates and the identification of molecules, which have a presently unknown effect on the migration process. For both objectives, we will employ novel experimental schemes. We will examine the role of proteins in achieving functional cell polarity compatible with efficient motility and response to directional cues, using unique techniques and analysis tools in the context of the living organism. The precise function of the identified proteins will be determined by combining mathematical tools aimed at quantitatively gauging the role of the molecules in conferring proper cell shape, biophysical methods aimed at measuring forces, rigidity and cytoplasm flow and determination of the effect on the organization of relevant structures using cryo electron tomography.
Together, this approach would provide a non-conventional understanding of cell migration by correlating structural, morphological and dynamic cellular properties with the ability of cells to effectively migrate towards their target.
Max ERC Funding
1 960 600 €
Duration
Start date: 2011-06-01, End date: 2017-05-31
Project acronym ChaperoneRegulome
Project ChaperoneRegulome: Understanding cell-type-specificity of chaperone regulation
Researcher (PI) Ritwick SAWARKAR
Host Institution (HI) MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV
Call Details Consolidator Grant (CoG), LS3, ERC-2018-COG
Summary Protein misfolding causes devastating health conditions such as neurodegeneration. Although the disease-causing protein is widely expressed, its misfolding occurs only in certain cell-types such as neurons. What governs the susceptibility of some tissues to misfolding is a fundamental question with biomedical relevance.
Molecular chaperones help cellular proteins fold into their native conformation. Despite the generality of their function, chaperones are differentially expressed across various tissues. Moreover exposure to misfolding stress changes chaperone expression in a cell-type-dependent manner. Thus cell-type-specific regulation of chaperones is a major determinant of susceptibility to misfolding. The molecular mechanisms governing chaperone levels in different cell-types are not understood, forming the basis of this proposal. We will take a multidisciplinary approach to address two key questions: (1) How are chaperone levels co-ordinated with tissue-specific demands on protein folding? (2) How do different cell-types regulate chaperone genes when exposed to the same misfolding stress?
Cellular chaperone levels and their response to misfolding stress are both driven by transcriptional changes and influenced by chromatin. The proposed work will bring the conceptual, technological and computational advances of chromatin/ transcription field to understand chaperone biology and misfolding diseases. Using in vivo mouse model and in vitro differentiation model, we will investigate molecular mechanisms that control chaperone levels in relevant tissues. Our work will provide insights into functional specialization of chaperones driven by tissue-specific folding demands. We will develop a novel and ambitious approach to assess protein-folding capacity in single cells moving the chaperone field beyond state-of-the-art. Thus by implementing genetic, computational and biochemical approaches, we aim to understand cell-type-specificity of chaperone regulation.
Summary
Protein misfolding causes devastating health conditions such as neurodegeneration. Although the disease-causing protein is widely expressed, its misfolding occurs only in certain cell-types such as neurons. What governs the susceptibility of some tissues to misfolding is a fundamental question with biomedical relevance.
Molecular chaperones help cellular proteins fold into their native conformation. Despite the generality of their function, chaperones are differentially expressed across various tissues. Moreover exposure to misfolding stress changes chaperone expression in a cell-type-dependent manner. Thus cell-type-specific regulation of chaperones is a major determinant of susceptibility to misfolding. The molecular mechanisms governing chaperone levels in different cell-types are not understood, forming the basis of this proposal. We will take a multidisciplinary approach to address two key questions: (1) How are chaperone levels co-ordinated with tissue-specific demands on protein folding? (2) How do different cell-types regulate chaperone genes when exposed to the same misfolding stress?
Cellular chaperone levels and their response to misfolding stress are both driven by transcriptional changes and influenced by chromatin. The proposed work will bring the conceptual, technological and computational advances of chromatin/ transcription field to understand chaperone biology and misfolding diseases. Using in vivo mouse model and in vitro differentiation model, we will investigate molecular mechanisms that control chaperone levels in relevant tissues. Our work will provide insights into functional specialization of chaperones driven by tissue-specific folding demands. We will develop a novel and ambitious approach to assess protein-folding capacity in single cells moving the chaperone field beyond state-of-the-art. Thus by implementing genetic, computational and biochemical approaches, we aim to understand cell-type-specificity of chaperone regulation.
Max ERC Funding
1 992 500 €
Duration
Start date: 2019-07-01, End date: 2024-06-30
Project acronym CHD-IPS
Project Modeling congenital heart disease (CHD) in ISL1+ cardiovascular progenitors from patient-specific iPS cells
Researcher (PI) Karl-Ludwig Laugwitz
Host Institution (HI) KLINIKUM RECHTS DER ISAR DER TECHNISCHEN UNIVERSITAT MUNCHEN
Call Details Starting Grant (StG), LS4, ERC-2010-StG_20091118
Summary Tetralogy of Fallot (TOF) is the most common congenital heart disease (CHD) occurring 1 in 3000 births. Genetic studies have identified numerous genes that are responsible for inherited and sporadic forms of TOF, most of which encode key molecules that are part of regulatory networks controlling heart development. The identification of two populations of cardiac precursors, one exclusively forming the left ventricle and the second the outflow tract, the right ventricle and the atria, has suggested a new approach to interpret CHDs, in particular in TOF, not as a defect in a specific gene, but rather as a defect in the formation, expansion, and differentiation of defined subsets of embryonic cardiac precursors. The LIM-homeodomain transcription factor ISL1 marks the second population of cardiac progenitors, but little is known about its downstream targets, and how causative genes of CHDs affect cell-fate decisions in the ISL1 lineage. The main goals of this research program are: (1) to decipher the functional role of Isl1 downstream targets identified by a genome-wide ChIP-Seq approach; (2) to generate induced pluripotent stem (iPS) cells from controls and patients affected by severe forms of TOF characterized by defects in heart compartments known to derive from ISL1 cardiac progenitors; (3) to direct these iPS cells to ISL1+ cardiovascular precursors and identify cell-surface makers enabling their antibody-based purification; and (4) to use TOF-iPS-derived ISL1+ progenitors as an unique in vitro model system for deciphering molecular mechanisms that govern the fates and differentiation of this progenitor lineage and determine the pathological phenotype seen in TOF. This work will shed light on the molecular mechanisms of ISL1+ cardiac progenitor lineage specification and will give important new insights into the mechanisms of how alterations in transcriptional and epigenetic programs translate to a distinct structural defect during cardiogenesis.
Summary
Tetralogy of Fallot (TOF) is the most common congenital heart disease (CHD) occurring 1 in 3000 births. Genetic studies have identified numerous genes that are responsible for inherited and sporadic forms of TOF, most of which encode key molecules that are part of regulatory networks controlling heart development. The identification of two populations of cardiac precursors, one exclusively forming the left ventricle and the second the outflow tract, the right ventricle and the atria, has suggested a new approach to interpret CHDs, in particular in TOF, not as a defect in a specific gene, but rather as a defect in the formation, expansion, and differentiation of defined subsets of embryonic cardiac precursors. The LIM-homeodomain transcription factor ISL1 marks the second population of cardiac progenitors, but little is known about its downstream targets, and how causative genes of CHDs affect cell-fate decisions in the ISL1 lineage. The main goals of this research program are: (1) to decipher the functional role of Isl1 downstream targets identified by a genome-wide ChIP-Seq approach; (2) to generate induced pluripotent stem (iPS) cells from controls and patients affected by severe forms of TOF characterized by defects in heart compartments known to derive from ISL1 cardiac progenitors; (3) to direct these iPS cells to ISL1+ cardiovascular precursors and identify cell-surface makers enabling their antibody-based purification; and (4) to use TOF-iPS-derived ISL1+ progenitors as an unique in vitro model system for deciphering molecular mechanisms that govern the fates and differentiation of this progenitor lineage and determine the pathological phenotype seen in TOF. This work will shed light on the molecular mechanisms of ISL1+ cardiac progenitor lineage specification and will give important new insights into the mechanisms of how alterations in transcriptional and epigenetic programs translate to a distinct structural defect during cardiogenesis.
Max ERC Funding
1 499 996 €
Duration
Start date: 2011-03-01, End date: 2017-02-28
Project acronym COMMOTS
Project Communication Motifs: Principles of bacterial communication in non-genetically diversified populations
Researcher (PI) Ilka Bischofs-Pfeifer
Host Institution (HI) RUPRECHT-KARLS-UNIVERSITAET HEIDELBERG
Call Details Starting Grant (StG), LS2, ERC-2010-StG_20091118
Summary Cell-to-cell communication is a central aspect for understanding how cells form and organize multi-cellular communities involving progressive cell specialization. Multi-cellularity cell specialization cell communication those keywords are frequently used to distinguish metazoans from bacteria. Yet bacteria can form morphologically complex multi-cellular communities, they can non-genetically diversify and they can communicate. This implies that even prokaryotic networks must possess the properties to facilitate these complex functions. Thus basic network features ( motifs ) determining these functions can be discovered and characterized from studying simpler bacterial networks. We want to focus on communication motifs that are present in the gene-regulatory network of Bacillus subtilis. Our proposed methodology involves a combination of quantitative fluorescence microscopy techniques (QFTLM, FRET), developmental assays, signal transduction studies in controlled micro-environments and information theory to quantitatively characterize communication motifs..
Summary
Cell-to-cell communication is a central aspect for understanding how cells form and organize multi-cellular communities involving progressive cell specialization. Multi-cellularity cell specialization cell communication those keywords are frequently used to distinguish metazoans from bacteria. Yet bacteria can form morphologically complex multi-cellular communities, they can non-genetically diversify and they can communicate. This implies that even prokaryotic networks must possess the properties to facilitate these complex functions. Thus basic network features ( motifs ) determining these functions can be discovered and characterized from studying simpler bacterial networks. We want to focus on communication motifs that are present in the gene-regulatory network of Bacillus subtilis. Our proposed methodology involves a combination of quantitative fluorescence microscopy techniques (QFTLM, FRET), developmental assays, signal transduction studies in controlled micro-environments and information theory to quantitatively characterize communication motifs..
Max ERC Funding
1 496 840 €
Duration
Start date: 2011-09-01, End date: 2016-08-31
