Project acronym CNTM
Project Cryptography on Non-Trusted Machines
Researcher (PI) Stefan Dziembowski
Host Institution (HI) UNIWERSYTET WARSZAWSKI
Call Details Starting Grant (StG), PE5, ERC-2007-StG
Summary This project is about the design of cryptographic schemes that are secure even if implemented on not-secure devices. The motivation for this problem comes from an observation that most of the real-life attacks on cryptographic devices do not break their mathematical foundations, but exploit vulnerabilities of their implementations. This concerns both the cryptographic software executed on PCs (that can be attacked by viruses), and the implementations on hardware (that can be subject to the side-channel attacks). Traditionally fixing this problem was left to the practitioners, since it was a common belief that theory cannot be of any help here. However, new exciting results in cryptography suggest that this view was too pessimistic: there exist methods to design cryptographic protocols in such a way that they are secure even if the hardware on which they are executed cannot be fully trusted. The goal of this project is to investigate these methods further, unify them in a solid mathematical theory (many of them were developed independently), and propose new ideas in this area. The project will be mostly theoretical (although some practical experiments may be performed). Our main interest lies within the theory of private circuits, bounded-retrieval model, physically-observable cryptography, and human-assisted cryptography. We view these theories just as the departing points, since the area is very fresh and we expect to soon witness completely new ideas in this field.
Summary
This project is about the design of cryptographic schemes that are secure even if implemented on not-secure devices. The motivation for this problem comes from an observation that most of the real-life attacks on cryptographic devices do not break their mathematical foundations, but exploit vulnerabilities of their implementations. This concerns both the cryptographic software executed on PCs (that can be attacked by viruses), and the implementations on hardware (that can be subject to the side-channel attacks). Traditionally fixing this problem was left to the practitioners, since it was a common belief that theory cannot be of any help here. However, new exciting results in cryptography suggest that this view was too pessimistic: there exist methods to design cryptographic protocols in such a way that they are secure even if the hardware on which they are executed cannot be fully trusted. The goal of this project is to investigate these methods further, unify them in a solid mathematical theory (many of them were developed independently), and propose new ideas in this area. The project will be mostly theoretical (although some practical experiments may be performed). Our main interest lies within the theory of private circuits, bounded-retrieval model, physically-observable cryptography, and human-assisted cryptography. We view these theories just as the departing points, since the area is very fresh and we expect to soon witness completely new ideas in this field.
Max ERC Funding
872 550 €
Duration
Start date: 2008-11-01, End date: 2013-10-31
Project acronym CoSI
Project Functional connectomics of the amygdala in social interactions of different valence
Researcher (PI) Ewelina KNAPSKA
Host Institution (HI) INSTYTUT BIOLOGII DOSWIADCZALNEJ IM. M. NENCKIEGO POLSKIEJ AKADEMII NAUK
Call Details Starting Grant (StG), LS5, ERC-2016-STG
Summary Understanding how brain controls social interactions is one of the central goals of neuroscience. Whereas social interactions and their effects on the emotional state of an individual are relatively well described at the behavioral level, much less is known about neural mechanisms involved in these very complex phenomena, especially in the amygdala, a key structure processing emotions in the brain.
Recent investigations, mainly on fear learning and extinction, have shown that there are highly specialized neuronal circuits within the amygdala that control specific behaviors. However, a high density of interconnections, both among amygdalar nuclei and between amygdalar nuclei and other brain regions, and the lack of a predictable distribution of functional cell types make defining behavioral functions of the amygdalar neuronal circuits challenging. Therefore, to understand how different neuronal circuits in the amygdala produce different behaviors tracing anatomical connections between activated neurons, i.e., the functional anatomy is needed.
Published data and our preliminary results suggest that within the amygdala there exist different neuronal circuits mediating social interactions of different valence (positive or negative affective significance) and that circuits controlling social and non-social emotions differ. Combining our recently developed behavioral models of adult, non-aggressive, same-sex social interactions with the methods of tracing anatomical connections between activated neurons, we plan to identify neural circuitry underlying social interactions of different emotional valence. This goal will be achieved by: (1) Characterizing functional anatomy of neuronal circuits in the amygdala underlying socially transferred emotions; (2) Examining role of the identified neuronal subpopulations in control of social behaviors; (3) Verifying role of matrix metalloproteinase-9-dependent neuronal subpopulations within the amygdala in social motivation.
Summary
Understanding how brain controls social interactions is one of the central goals of neuroscience. Whereas social interactions and their effects on the emotional state of an individual are relatively well described at the behavioral level, much less is known about neural mechanisms involved in these very complex phenomena, especially in the amygdala, a key structure processing emotions in the brain.
Recent investigations, mainly on fear learning and extinction, have shown that there are highly specialized neuronal circuits within the amygdala that control specific behaviors. However, a high density of interconnections, both among amygdalar nuclei and between amygdalar nuclei and other brain regions, and the lack of a predictable distribution of functional cell types make defining behavioral functions of the amygdalar neuronal circuits challenging. Therefore, to understand how different neuronal circuits in the amygdala produce different behaviors tracing anatomical connections between activated neurons, i.e., the functional anatomy is needed.
Published data and our preliminary results suggest that within the amygdala there exist different neuronal circuits mediating social interactions of different valence (positive or negative affective significance) and that circuits controlling social and non-social emotions differ. Combining our recently developed behavioral models of adult, non-aggressive, same-sex social interactions with the methods of tracing anatomical connections between activated neurons, we plan to identify neural circuitry underlying social interactions of different emotional valence. This goal will be achieved by: (1) Characterizing functional anatomy of neuronal circuits in the amygdala underlying socially transferred emotions; (2) Examining role of the identified neuronal subpopulations in control of social behaviors; (3) Verifying role of matrix metalloproteinase-9-dependent neuronal subpopulations within the amygdala in social motivation.
Max ERC Funding
1 312 500 €
Duration
Start date: 2016-12-01, End date: 2021-11-30
Project acronym McHAP
Project Entrapment of Hypoxic Cancer by Macrophages Loaded with HAP
Researcher (PI) Magdalena KROL
Host Institution (HI) SZKOLA GLOWNA GOSPODARSTWA WIEJSKIEGO
Call Details Starting Grant (StG), LS9, ERC-2016-STG
Summary The proposed project seeks to open a new research front within the field of drug delivery to the solid tumours. Unsatisfactory response of tumours to chemotherapy is mainly related to impaired diffusion of the anticancer drug because of decreased drug uptake due to poor vasculature. Moreover, the drug is not able to penetrate the most hypoxic sites. Cells from these ‘untreated’ sites are responsible for relapse and metastasis. However, these avascular regions attract macrophages that migrate even to areas far away from blood vessels. Therefore, they might constitute a unique delivery system of drug containing particles to these parts of the tumour mass. A promising example of such particles that could be used are ferritins, whose caged architecture allows for efficient drug encapsulation and whose uptake from macrophage cells has been well demonstrated. My recent ground breaking finding was that macrophages are also able to specifically and actively transfer these taken up ferritins (loaded with the compound of choice) to cancer cells. Thus, these preliminary results indicate the possibility to use macrophages to deliver ferritin encapsulated compounds directly to the tumour cells even in its hypoxic areas. Then, the use of hypoxia-activated prodrugs (HAP) which are selectively activated only in hypoxic regions will be exploited in order to make cancer therapy safer. However, the molecular mechanism of ferritin uptake by macrophages, their storage, and transport to the cancer cells represent key issues to be investigated and pave the way to the experimental design of the present project.
In the present project, we will develop and characterize a completely new and modern approach to anticancer therapy and drug delivery. As such we expect to be able to precisely administer drugs to the tumour site (even to the hypoxic regions) where it is activated by tumour-specific conditions, avoiding side effects of anticancer therapy.
Summary
The proposed project seeks to open a new research front within the field of drug delivery to the solid tumours. Unsatisfactory response of tumours to chemotherapy is mainly related to impaired diffusion of the anticancer drug because of decreased drug uptake due to poor vasculature. Moreover, the drug is not able to penetrate the most hypoxic sites. Cells from these ‘untreated’ sites are responsible for relapse and metastasis. However, these avascular regions attract macrophages that migrate even to areas far away from blood vessels. Therefore, they might constitute a unique delivery system of drug containing particles to these parts of the tumour mass. A promising example of such particles that could be used are ferritins, whose caged architecture allows for efficient drug encapsulation and whose uptake from macrophage cells has been well demonstrated. My recent ground breaking finding was that macrophages are also able to specifically and actively transfer these taken up ferritins (loaded with the compound of choice) to cancer cells. Thus, these preliminary results indicate the possibility to use macrophages to deliver ferritin encapsulated compounds directly to the tumour cells even in its hypoxic areas. Then, the use of hypoxia-activated prodrugs (HAP) which are selectively activated only in hypoxic regions will be exploited in order to make cancer therapy safer. However, the molecular mechanism of ferritin uptake by macrophages, their storage, and transport to the cancer cells represent key issues to be investigated and pave the way to the experimental design of the present project.
In the present project, we will develop and characterize a completely new and modern approach to anticancer therapy and drug delivery. As such we expect to be able to precisely administer drugs to the tumour site (even to the hypoxic regions) where it is activated by tumour-specific conditions, avoiding side effects of anticancer therapy.
Max ERC Funding
1 413 750 €
Duration
Start date: 2017-01-01, End date: 2021-12-31
Project acronym NERCOMP
Project Structural studies of Nucleotide Excision Repair complexes
Researcher (PI) Marcin Nowotny
Host Institution (HI) INTERNATIONAL INSTITUTE OF MOLECULAR AND CELL BIOLOGY
Call Details Starting Grant (StG), LS1, ERC-2011-StG_20101109
Summary "DNA damage caused by chemical and physical factors can lead to detrimental effects to the cell and must be corrected. One of the primary pathways to achieve this repair is nucleotide excision repair (NER). In NER, the DNA damage is first located, a stretch of bases harboring the lesion is removed, and the gap is filled by a DNA polymerase. The unique feature of NER is its ability to correct a wide spectrum of DNA modifications of different sizes and chemical structures.
The aim of the project is to structurally and biochemically characterize protein complexes involved in NER pathways in bacteria and eukaryotes.
In bacterial NER, a complex of UvrA and UvrB proteins locates the damage and verifies its presence. In the first part of the project we plan to determine the crystal and small-angle X-ray scattering (SAXS) structures of a UvrA-UvrB-DNA complex to elucidate the details of the mechanism of the first steps of bacterial NER.
In eukaryotic NER, the 3′ incision is executed by XPG/Rad2 protein. Currently, no structural information is available for this protein. In the second part of the project, we plan to solve the crystal structures of XPG/Rad2 nuclease in apo form and in complex with the DNA substrate to elucidate the mechanism of the 3′ cut. We also plan to determine the structure of XPG/Rad2 in complex with the XPG/Rad2-binding domain from the p62 component of TFIIH, which will be an important building block for the determination of the architecture of the eukaryotic NER pre-incision complex.
The third part of the project will elucidate the structure and mechanism of the Rad16-Rad7 yeast NER complex. It is implicated in numerous stages of NER, from damage detection to ubiquitination of other NER components. We plan to solve the crystal structures of the Rad16-Rad7 alone and in complexes with DNA or partner protein Abf1 to elucidate the mechanisms of various activities of Rad16-Rad7 and help design experiments that could test the in vivo function of this complex."
Summary
"DNA damage caused by chemical and physical factors can lead to detrimental effects to the cell and must be corrected. One of the primary pathways to achieve this repair is nucleotide excision repair (NER). In NER, the DNA damage is first located, a stretch of bases harboring the lesion is removed, and the gap is filled by a DNA polymerase. The unique feature of NER is its ability to correct a wide spectrum of DNA modifications of different sizes and chemical structures.
The aim of the project is to structurally and biochemically characterize protein complexes involved in NER pathways in bacteria and eukaryotes.
In bacterial NER, a complex of UvrA and UvrB proteins locates the damage and verifies its presence. In the first part of the project we plan to determine the crystal and small-angle X-ray scattering (SAXS) structures of a UvrA-UvrB-DNA complex to elucidate the details of the mechanism of the first steps of bacterial NER.
In eukaryotic NER, the 3′ incision is executed by XPG/Rad2 protein. Currently, no structural information is available for this protein. In the second part of the project, we plan to solve the crystal structures of XPG/Rad2 nuclease in apo form and in complex with the DNA substrate to elucidate the mechanism of the 3′ cut. We also plan to determine the structure of XPG/Rad2 in complex with the XPG/Rad2-binding domain from the p62 component of TFIIH, which will be an important building block for the determination of the architecture of the eukaryotic NER pre-incision complex.
The third part of the project will elucidate the structure and mechanism of the Rad16-Rad7 yeast NER complex. It is implicated in numerous stages of NER, from damage detection to ubiquitination of other NER components. We plan to solve the crystal structures of the Rad16-Rad7 alone and in complexes with DNA or partner protein Abf1 to elucidate the mechanisms of various activities of Rad16-Rad7 and help design experiments that could test the in vivo function of this complex."
Max ERC Funding
1 498 000 €
Duration
Start date: 2012-01-01, End date: 2017-12-31
Project acronym PAPS&PUPS
Project Regulation of Gene Expression by non-canonical poly(A) and poly(U) polymerases
Researcher (PI) Andrzej Dziembowski
Host Institution (HI) INSTYTUT BIOCHEMII I BIOFIZYKI POLSKIEJ AKADEMII NAUK
Call Details Starting Grant (StG), LS1, ERC-2012-StG_20111109
Summary In eukaryotes, almost all RNA molecules are processed at their 3’ ends and most mRNAs are polyadenylated in the nucleus by canonical poly(A) polymerases (PAPs). Recently, several new non-canonical poly(A) (ncPAPs) and poly(U) polymerases (PUPs) have been discovered that have more specific regulatory roles. In contrast to canonical ones, their functions are more diverse; some induce RNA decay while others, especially cytoplasmic ncPAPs, activate translationally dormant deadenylated mRNAs. Knowledge about ncPAPs and PUPs is very scarce and there are crucial questions about their functions that need to be addressed.
The project has 3 parts:
1) Functional analysis of FAM46 proteins, which, according to our preliminary data, constitute a new family of active poly(A) polymerases. FAM46C is frequently mutated in myelomas and mutations in its mouse orthologue cause anaemia, thus demonstrating important biological functions of this unexplored family of proteins.
2) Elucidation of the functions of all known vertebrate ncPAPs and PUPs (7 previously known and 4 members of FAM46 family) using the chicken DT40 cell line as a model system. DT40 has an exceptionally high rate of homologous recombination, allowing easy gene targeting and generation of multiple knockouts that facilitate the study of proteins with overlapping functions.
3) Cytoplasmic polyadenylation of dormant mRNA molecules activates translation in neurons, gametes and reticulocytes. In neurons, it occurs in axons and dendrites following synaptic stimulation while in oocytes, it is induced by progesterone. The exact impact on gene expression is not well defined due to a lack of technologies identifying cytoplasmically polyadenylated transcripts. We will develop a novel detection method for ongoing RNA polyadenylation to assess the biological significance of cytoplasmic polyadenylation. This part of the project will be developed using mouse synaptoneurosomes and then transferred to reticulocytes and possibly oocytes.
Summary
In eukaryotes, almost all RNA molecules are processed at their 3’ ends and most mRNAs are polyadenylated in the nucleus by canonical poly(A) polymerases (PAPs). Recently, several new non-canonical poly(A) (ncPAPs) and poly(U) polymerases (PUPs) have been discovered that have more specific regulatory roles. In contrast to canonical ones, their functions are more diverse; some induce RNA decay while others, especially cytoplasmic ncPAPs, activate translationally dormant deadenylated mRNAs. Knowledge about ncPAPs and PUPs is very scarce and there are crucial questions about their functions that need to be addressed.
The project has 3 parts:
1) Functional analysis of FAM46 proteins, which, according to our preliminary data, constitute a new family of active poly(A) polymerases. FAM46C is frequently mutated in myelomas and mutations in its mouse orthologue cause anaemia, thus demonstrating important biological functions of this unexplored family of proteins.
2) Elucidation of the functions of all known vertebrate ncPAPs and PUPs (7 previously known and 4 members of FAM46 family) using the chicken DT40 cell line as a model system. DT40 has an exceptionally high rate of homologous recombination, allowing easy gene targeting and generation of multiple knockouts that facilitate the study of proteins with overlapping functions.
3) Cytoplasmic polyadenylation of dormant mRNA molecules activates translation in neurons, gametes and reticulocytes. In neurons, it occurs in axons and dendrites following synaptic stimulation while in oocytes, it is induced by progesterone. The exact impact on gene expression is not well defined due to a lack of technologies identifying cytoplasmically polyadenylated transcripts. We will develop a novel detection method for ongoing RNA polyadenylation to assess the biological significance of cytoplasmic polyadenylation. This part of the project will be developed using mouse synaptoneurosomes and then transferred to reticulocytes and possibly oocytes.
Max ERC Funding
1 500 000 €
Duration
Start date: 2013-02-01, End date: 2019-01-31
Project acronym RNA+P=123D
Project Breaking the code of RNA sequence-structure-function relationships: New strategies and tools for modelling and engineering of RNA and RNA-protein complexes
Researcher (PI) Janusz Marek Bujnicki
Host Institution (HI) INTERNATIONAL INSTITUTE OF MOLECULAR AND CELL BIOLOGY
Call Details Starting Grant (StG), LS2, ERC-2010-StG_20091118
Summary Ribonucleic acid (RNA) is a large class of macromolecules that plays a key role in the communication of biological information between DNA and proteins. RNAs have been also shown to perform enzymatic catalysis. Recently, numerous new RNAs have been identified and shown to perform essential regulatory roles in cells.
As with proteins, the function of RNA depends on its structure, which in turn is encoded in the linear sequence. The secondary structure of RNA is defined by canonical base pairs, while the tertiary (3D) structure is formed mostly by non-canonical base pairs that form three-dimensional motifs. RNA is similar to proteins in that the development of methods for 3D structure prediction is absolutely essential to functionally interpret the information encoded in the primary sequence of genes. For proteins there are many freely available methods for automated protein 3D structure prediction that produce reasonably accurate and useful models. There are also methods for objective assessment of the protein model quality. However, there are no such methods for automated 3D structure modelling of RNA. There are only methods for RNA secondary structure prediction and a few methods for manual 3D modelling, but no automated methods for comparative modelling, fold-recognition of RNA, and evaluation of models. Only recently a few methods for de novo folding of RNA appeared, but they can provide useful models only for very short molecules.
Recently, inspired by methodology for protein modelling, we have developed prototype tools for both comparative (template-based) and de novo (template-free) modelling of RNA, which allow for building models for very large RNA molecules. These tools will be further optimized and tested. The major goal is to developed tools for RNA modelling to the level of existing protein-modelling methods and to combine RNA and protein-centric methods to allow multiscale modelling of protein-nucleic acid complexes, either with or without the aid of experimental data. This proposal also includes the development of methods for the assessment of model quality and benchmarking of methods. The software tools and the theoretical predictions will be extensively tested (also by experimental verification of models), optimized and applied to biologically and medically relevant RNAs and complexes.
In one sentence: The aim of this project is to use bioinformatics and experimental methods to crack the code of sequence-structure relationships in RNA and RNA-protein complexes and to revolutionise the field of RNA & RNP modelling and structure/function analyses.
Summary
Ribonucleic acid (RNA) is a large class of macromolecules that plays a key role in the communication of biological information between DNA and proteins. RNAs have been also shown to perform enzymatic catalysis. Recently, numerous new RNAs have been identified and shown to perform essential regulatory roles in cells.
As with proteins, the function of RNA depends on its structure, which in turn is encoded in the linear sequence. The secondary structure of RNA is defined by canonical base pairs, while the tertiary (3D) structure is formed mostly by non-canonical base pairs that form three-dimensional motifs. RNA is similar to proteins in that the development of methods for 3D structure prediction is absolutely essential to functionally interpret the information encoded in the primary sequence of genes. For proteins there are many freely available methods for automated protein 3D structure prediction that produce reasonably accurate and useful models. There are also methods for objective assessment of the protein model quality. However, there are no such methods for automated 3D structure modelling of RNA. There are only methods for RNA secondary structure prediction and a few methods for manual 3D modelling, but no automated methods for comparative modelling, fold-recognition of RNA, and evaluation of models. Only recently a few methods for de novo folding of RNA appeared, but they can provide useful models only for very short molecules.
Recently, inspired by methodology for protein modelling, we have developed prototype tools for both comparative (template-based) and de novo (template-free) modelling of RNA, which allow for building models for very large RNA molecules. These tools will be further optimized and tested. The major goal is to developed tools for RNA modelling to the level of existing protein-modelling methods and to combine RNA and protein-centric methods to allow multiscale modelling of protein-nucleic acid complexes, either with or without the aid of experimental data. This proposal also includes the development of methods for the assessment of model quality and benchmarking of methods. The software tools and the theoretical predictions will be extensively tested (also by experimental verification of models), optimized and applied to biologically and medically relevant RNAs and complexes.
In one sentence: The aim of this project is to use bioinformatics and experimental methods to crack the code of sequence-structure relationships in RNA and RNA-protein complexes and to revolutionise the field of RNA & RNP modelling and structure/function analyses.
Max ERC Funding
1 500 000 €
Duration
Start date: 2011-01-01, End date: 2015-12-31
Project acronym STIMUNO
Project Searching for novel strategies improving cancer immunotherapy
Researcher (PI) Magdalena WINIARSKA
Host Institution (HI) WARSZAWSKI UNIWERSYTET MEDYCZNY
Call Details Starting Grant (StG), LS4, ERC-2018-STG
Summary The main goal of this project is to explore new fundamental pathways involved in the regulation of antitumor immune response. Since the immunosuppressive tumor microenvironment constitutes a key barrier to effective immunotherapy, our predominant ambition is to characterize novel, hitherto unknown metabolic changes that can support the survival of tumor cells and the escape from the immune surveillance.
We have recently discovered a new metabolite within tumor microenvironment with a robust ability to inhibit the activity of immune cells and their potential to kill target tumor cells. Within the project, we plan to corroborate on our preliminary findings in order to establish the role of this factor in mitigating antitumor immune response. To this end, we will determine the level of its production within tumors in murine models. Moreover, we will relate these findings to human data by analysing the immune milieu and the expression of enzymes involved in generation of this metabolic agent in a cohort of cancer patients. We will also investigate the mechanisms by which this factor could perturb the functions of tumor-infiltrating effector cells.
Finally, we aspire to use the knowledge gained during the implementation of this project to propose innovative therapeutic solutions. Specifically, we will investigate whether and how the inhibition of selected enzymes involved in the generation of this new metabolic checkpoint can impact on the efficacy of immunotherapeutic agents, including immune checkpoint inhibitors, arginase inhibitors as well as adoptive therapy with CAR-T cells and CAR-NK cells. We strongly believe that by achieving the goals of our project we will make a significant step forward in order to develop and to design cutting-edge therapeutic strategies. These compelling solutions would further improve the efficacy of tumor immunotherapy, thus contributing to a breakthrough advance in cancer treatment.
Summary
The main goal of this project is to explore new fundamental pathways involved in the regulation of antitumor immune response. Since the immunosuppressive tumor microenvironment constitutes a key barrier to effective immunotherapy, our predominant ambition is to characterize novel, hitherto unknown metabolic changes that can support the survival of tumor cells and the escape from the immune surveillance.
We have recently discovered a new metabolite within tumor microenvironment with a robust ability to inhibit the activity of immune cells and their potential to kill target tumor cells. Within the project, we plan to corroborate on our preliminary findings in order to establish the role of this factor in mitigating antitumor immune response. To this end, we will determine the level of its production within tumors in murine models. Moreover, we will relate these findings to human data by analysing the immune milieu and the expression of enzymes involved in generation of this metabolic agent in a cohort of cancer patients. We will also investigate the mechanisms by which this factor could perturb the functions of tumor-infiltrating effector cells.
Finally, we aspire to use the knowledge gained during the implementation of this project to propose innovative therapeutic solutions. Specifically, we will investigate whether and how the inhibition of selected enzymes involved in the generation of this new metabolic checkpoint can impact on the efficacy of immunotherapeutic agents, including immune checkpoint inhibitors, arginase inhibitors as well as adoptive therapy with CAR-T cells and CAR-NK cells. We strongly believe that by achieving the goals of our project we will make a significant step forward in order to develop and to design cutting-edge therapeutic strategies. These compelling solutions would further improve the efficacy of tumor immunotherapy, thus contributing to a breakthrough advance in cancer treatment.
Max ERC Funding
1 498 750 €
Duration
Start date: 2019-03-01, End date: 2024-02-29
