Project acronym ABC
Project Targeting Multidrug Resistant Cancer
Researcher (PI) Gergely Szakacs
Host Institution (HI) MAGYAR TUDOMANYOS AKADEMIA TERMESZETTUDOMANYI KUTATOKOZPONT
Call Details Starting Grant (StG), LS7, ERC-2010-StG_20091118
Summary Despite considerable advances in drug discovery, resistance to anticancer chemotherapy confounds the effective treatment of patients. Cancer cells can acquire broad cross-resistance to mechanistically and structurally unrelated drugs. P-glycoprotein (Pgp) actively extrudes many types of drugs from cancer cells, thereby conferring resistance to those agents. The central tenet of my work is that Pgp, a universally accepted biomarker of drug resistance, should in addition be considered as a molecular target of multidrug-resistant (MDR) cancer cells. Successful targeting of MDR cells would reduce the tumor burden and would also enable the elimination of ABC transporter-overexpressing cancer stem cells that are responsible for the replenishment of tumors. The proposed project is based on the following observations:
- First, by using a pharmacogenomic approach, I have revealed the hidden vulnerability of MDRcells (Szakács et al. 2004, Cancer Cell 6, 129-37);
- Second, I have identified a series of MDR-selective compounds with increased toxicity toPgp-expressing cells
(Turk et al.,Cancer Res, 2009. 69(21));
- Third, I have shown that MDR-selective compounds can be used to prevent theemergence of MDR (Ludwig, Szakács et al. 2006, Cancer Res 66, 4808-15);
- Fourth, we have generated initial pharmacophore models for cytotoxicity and MDR-selectivity (Hall et al. 2009, J Med Chem 52, 3191-3204).
I propose a comprehensive series of studies that will address thefollowing critical questions:
- First, what is the scope of MDR-selective compounds?
- Second, what is their mechanism of action?
- Third, what is the optimal therapeutic modality?
Extensive biological, pharmacological and bioinformatic analyses will be utilized to address four major specific aims. These aims address basic questions concerning the physiology of MDR ABC transporters in determining the mechanism of action of MDR-selective compounds, setting the stage for a fresh therapeutic approach that may eventually translate into improved patient care.
Summary
Despite considerable advances in drug discovery, resistance to anticancer chemotherapy confounds the effective treatment of patients. Cancer cells can acquire broad cross-resistance to mechanistically and structurally unrelated drugs. P-glycoprotein (Pgp) actively extrudes many types of drugs from cancer cells, thereby conferring resistance to those agents. The central tenet of my work is that Pgp, a universally accepted biomarker of drug resistance, should in addition be considered as a molecular target of multidrug-resistant (MDR) cancer cells. Successful targeting of MDR cells would reduce the tumor burden and would also enable the elimination of ABC transporter-overexpressing cancer stem cells that are responsible for the replenishment of tumors. The proposed project is based on the following observations:
- First, by using a pharmacogenomic approach, I have revealed the hidden vulnerability of MDRcells (Szakács et al. 2004, Cancer Cell 6, 129-37);
- Second, I have identified a series of MDR-selective compounds with increased toxicity toPgp-expressing cells
(Turk et al.,Cancer Res, 2009. 69(21));
- Third, I have shown that MDR-selective compounds can be used to prevent theemergence of MDR (Ludwig, Szakács et al. 2006, Cancer Res 66, 4808-15);
- Fourth, we have generated initial pharmacophore models for cytotoxicity and MDR-selectivity (Hall et al. 2009, J Med Chem 52, 3191-3204).
I propose a comprehensive series of studies that will address thefollowing critical questions:
- First, what is the scope of MDR-selective compounds?
- Second, what is their mechanism of action?
- Third, what is the optimal therapeutic modality?
Extensive biological, pharmacological and bioinformatic analyses will be utilized to address four major specific aims. These aims address basic questions concerning the physiology of MDR ABC transporters in determining the mechanism of action of MDR-selective compounds, setting the stage for a fresh therapeutic approach that may eventually translate into improved patient care.
Max ERC Funding
1 499 640 €
Duration
Start date: 2012-01-01, End date: 2016-12-31
Project acronym ANALYTIC
Project ANALYTIC PROPERTIES OF INFINITE GROUPS:
limits, curvature, and randomness
Researcher (PI) Gulnara Arzhantseva
Host Institution (HI) UNIVERSITAT WIEN
Call Details Starting Grant (StG), PE1, ERC-2010-StG_20091028
Summary The overall goal of this project is to develop new concepts and techniques in geometric and asymptotic group theory for a systematic study of the analytic properties of discrete groups. These are properties depending on the unitary representation theory of the group. The fundamental examples are amenability, discovered by von Neumann in 1929, and property (T), introduced by Kazhdan in 1967.
My main objective is to establish the precise relations between groups recently appeared in K-theory and topology such as C*-exact groups and groups coarsely embeddable into a Hilbert space, versus those discovered in ergodic theory and operator algebra, for example, sofic and hyperlinear groups. This is a first ever attempt to confront the analytic behavior of so different nature. I plan to work on crucial open questions: Is every coarsely embeddable group C*-exact? Is every group sofic? Is every hyperlinear group sofic?
My motivation is two-fold:
- Many outstanding conjectures were recently solved for these groups, e.g. the Novikov conjecture (1965) for coarsely embeddable groups by Yu in 2000 and the Gottschalk surjunctivity conjecture (1973) for sofic groups by Gromov in 1999. However, their group-theoretical structure remains mysterious.
- In recent years, geometric group theory has undergone significant changes, mainly due to the growing impact of this theory on other branches of mathematics. However, the interplay between geometric, asymptotic, and analytic group properties has not yet been fully understood.
The main innovative contribution of this proposal lies in the interaction between 3 axes: (i) limits of groups, in the space of marked groups or metric ultralimits; (ii) analytic properties of groups with curvature, of lacunary or relatively hyperbolic groups; (iii) random groups, in a topological or statistical meaning. As a result, I will describe the above apparently unrelated classes of groups in a unified way and will detail their algebraic behavior.
Summary
The overall goal of this project is to develop new concepts and techniques in geometric and asymptotic group theory for a systematic study of the analytic properties of discrete groups. These are properties depending on the unitary representation theory of the group. The fundamental examples are amenability, discovered by von Neumann in 1929, and property (T), introduced by Kazhdan in 1967.
My main objective is to establish the precise relations between groups recently appeared in K-theory and topology such as C*-exact groups and groups coarsely embeddable into a Hilbert space, versus those discovered in ergodic theory and operator algebra, for example, sofic and hyperlinear groups. This is a first ever attempt to confront the analytic behavior of so different nature. I plan to work on crucial open questions: Is every coarsely embeddable group C*-exact? Is every group sofic? Is every hyperlinear group sofic?
My motivation is two-fold:
- Many outstanding conjectures were recently solved for these groups, e.g. the Novikov conjecture (1965) for coarsely embeddable groups by Yu in 2000 and the Gottschalk surjunctivity conjecture (1973) for sofic groups by Gromov in 1999. However, their group-theoretical structure remains mysterious.
- In recent years, geometric group theory has undergone significant changes, mainly due to the growing impact of this theory on other branches of mathematics. However, the interplay between geometric, asymptotic, and analytic group properties has not yet been fully understood.
The main innovative contribution of this proposal lies in the interaction between 3 axes: (i) limits of groups, in the space of marked groups or metric ultralimits; (ii) analytic properties of groups with curvature, of lacunary or relatively hyperbolic groups; (iii) random groups, in a topological or statistical meaning. As a result, I will describe the above apparently unrelated classes of groups in a unified way and will detail their algebraic behavior.
Max ERC Funding
1 065 500 €
Duration
Start date: 2011-04-01, End date: 2016-03-31
Project acronym CosNeD
Project Radio wave propagation in heterogeneous media: implications on the electronics of Cosmic Neutrino Detectors
Researcher (PI) Alina Mihaela BADESCU
Host Institution (HI) UNIVERSITATEA POLITEHNICA DIN BUCURESTI
Call Details Starting Grant (StG), PE7, ERC-2016-STG
Summary Detection of cosmic neutrinos can answer very important questions related to some extremely energetic yet unexplained astrophysical sources such as: compact binary stars, accreting black holes, supernovae etc., key elements in understanding the evolution and fate of the Universe. Moreover, these particles carry the highest
energies per particle known to man, impossible to achieve in any present or foreseen man made accelerator devices thus their detection can test and probe extreme high energy physics.
One of the newest techniques for measuring high energy cosmic neutrinos regards their radio detection in natural salt mines. A first and essential step is to determine experimentally the radio wave attenuation length in salt mines, and this will represent the main goal of this project. The results shall be used to estimate the implications on the construction of the detector. The outcome of this project may rejuvenate the radio detection in salt technique and be a compelling case for Romanian involvement. The same measurements can be used: to validate and improve previous work on theoretical simulation models of propagation in heterogeneous media –a regime not very well understood (which represents another goal of the project), and to study the behavior of classical antennas in non-conventional media (the third major goal).
The results to be obtained would be immediately relevant in determination of the key parameters that describe a cosmic neutrino detector, its performances and limitations. The events detected by such a telescope will allow identification of individual sources indicating a step forward in “neutrino astronomy”. The extensive propagation and antenna behavior studies in heterogeneous media will be in the direct interest for the scientific community and have a prompt impact in telecommunications theory and industry.
Summary
Detection of cosmic neutrinos can answer very important questions related to some extremely energetic yet unexplained astrophysical sources such as: compact binary stars, accreting black holes, supernovae etc., key elements in understanding the evolution and fate of the Universe. Moreover, these particles carry the highest
energies per particle known to man, impossible to achieve in any present or foreseen man made accelerator devices thus their detection can test and probe extreme high energy physics.
One of the newest techniques for measuring high energy cosmic neutrinos regards their radio detection in natural salt mines. A first and essential step is to determine experimentally the radio wave attenuation length in salt mines, and this will represent the main goal of this project. The results shall be used to estimate the implications on the construction of the detector. The outcome of this project may rejuvenate the radio detection in salt technique and be a compelling case for Romanian involvement. The same measurements can be used: to validate and improve previous work on theoretical simulation models of propagation in heterogeneous media –a regime not very well understood (which represents another goal of the project), and to study the behavior of classical antennas in non-conventional media (the third major goal).
The results to be obtained would be immediately relevant in determination of the key parameters that describe a cosmic neutrino detector, its performances and limitations. The events detected by such a telescope will allow identification of individual sources indicating a step forward in “neutrino astronomy”. The extensive propagation and antenna behavior studies in heterogeneous media will be in the direct interest for the scientific community and have a prompt impact in telecommunications theory and industry.
Max ERC Funding
185 925 €
Duration
Start date: 2016-11-01, End date: 2018-10-31
Project acronym COYOTE
Project Coherent Optics Everywhere: a New Dawn for Photonic Networks
Researcher (PI) Bernhard SCHRENK
Host Institution (HI) AIT AUSTRIAN INSTITUTE OF TECHNOLOGY GMBH
Call Details Starting Grant (StG), PE7, ERC-2018-STG
Summary The widespread adoption of the Internet and its influence on our daily life is unquestioned. Global Zettabyte traffic has rendered photonics as indispensable for the communication infrastructure. While direct signal detection has been dismissed in radio communications decades ago, it prevails in short- and medium-reach optics in virtue of its simplicity. In such an environment photonics can only rely on incremental improvements, whereas it desperately seeks for disruptive concepts.
COYOTE envisions a novel coherent homodyne transceiver concept for analogue signals and access to higher-order formats with efficiencies of 10 bits/symbol. On top of this, high-fidelity transport of multi-band 5G radio signals in the millimetre-wave range up to 100 GHz will be enabled by analogue coherent photonics while mitigating energy-hungry digital signal processing. COYOTE takes one more leap and dares the contradictory full-duplex data transmission in virtue of its novel reception engine to ultimately guarantee a lean solution with greatly simplified yet flexible “hardware”.
The key asset of COYOTE’s coherent engine will be a locked laser with improved coherence characteristics together with a flexible modulator-detector element, which is capable to emulate direct-detection systems in a transparent way while giving birth to novel networking concepts. Exploration of the 3D Stokes and 2D quadrature spaces through a segmented receiver architecture will boost the spectral efficiency to >10 bits/s/Hz.
It is the lean and yet efficient coherent transceiver methodology of COYOTE that will remove the currently existing boundary between direct-detection and coherent systems in the midst of network reaches. By coherently “reviving” these telecom segments of integrated wireline-wireless access networks, optical interconnects for intra-datacentre connectivity and even quantum communication, an order-of-magnitude improvement in terms of spectral efficiency x reach product will be gained.
Summary
The widespread adoption of the Internet and its influence on our daily life is unquestioned. Global Zettabyte traffic has rendered photonics as indispensable for the communication infrastructure. While direct signal detection has been dismissed in radio communications decades ago, it prevails in short- and medium-reach optics in virtue of its simplicity. In such an environment photonics can only rely on incremental improvements, whereas it desperately seeks for disruptive concepts.
COYOTE envisions a novel coherent homodyne transceiver concept for analogue signals and access to higher-order formats with efficiencies of 10 bits/symbol. On top of this, high-fidelity transport of multi-band 5G radio signals in the millimetre-wave range up to 100 GHz will be enabled by analogue coherent photonics while mitigating energy-hungry digital signal processing. COYOTE takes one more leap and dares the contradictory full-duplex data transmission in virtue of its novel reception engine to ultimately guarantee a lean solution with greatly simplified yet flexible “hardware”.
The key asset of COYOTE’s coherent engine will be a locked laser with improved coherence characteristics together with a flexible modulator-detector element, which is capable to emulate direct-detection systems in a transparent way while giving birth to novel networking concepts. Exploration of the 3D Stokes and 2D quadrature spaces through a segmented receiver architecture will boost the spectral efficiency to >10 bits/s/Hz.
It is the lean and yet efficient coherent transceiver methodology of COYOTE that will remove the currently existing boundary between direct-detection and coherent systems in the midst of network reaches. By coherently “reviving” these telecom segments of integrated wireline-wireless access networks, optical interconnects for intra-datacentre connectivity and even quantum communication, an order-of-magnitude improvement in terms of spectral efficiency x reach product will be gained.
Max ERC Funding
1 500 000 €
Duration
Start date: 2019-01-01, End date: 2023-12-31
Project acronym EPIDELAY
Project Delay differential models and transmission dynamics of infectious diseases
Researcher (PI) Gergely Röst
Host Institution (HI) SZEGEDI TUDOMANYEGYETEM
Call Details Starting Grant (StG), PE1, ERC-2010-StG_20091028
Summary The aim of this project is to develop and analyse infinite dimensional dynamical models for the transmission dynamics and propagation of infectious diseases. We use an integrated approach which spans from the abstract theory of functional differential equations to the practical problems of epidemiology, with serious implications to public health policy, prevention, control and mitigation strategies in cases such as the ongoing battle against the nascent H1N1 pandemic.
Delay differential equations are one of the most powerful mathematical modeling tools and they arise naturally in various applications from life sciences to engineering and physics, whenever temporal delays are important. In abstract terms, functional differential equations describe dynamical systems, when their evolution depends on the solution at prior times.
The central theme of this project is to forge strong links between the abstract theory of delay differential equations and practical aspects of epidemiology. Our research will combine competencies in different fields of mathematics and embrace theoretical issues as well as real life applications.
In particular, the theory of equations with state dependent delays is extremely challenging, and this field is at present on the verge of a breakthrough. Developing new theories in this area and connecting them to relevant applications would go far beyond the current research frontier of mathematical epidemiology and could open a new chapter in disease modeling.
Summary
The aim of this project is to develop and analyse infinite dimensional dynamical models for the transmission dynamics and propagation of infectious diseases. We use an integrated approach which spans from the abstract theory of functional differential equations to the practical problems of epidemiology, with serious implications to public health policy, prevention, control and mitigation strategies in cases such as the ongoing battle against the nascent H1N1 pandemic.
Delay differential equations are one of the most powerful mathematical modeling tools and they arise naturally in various applications from life sciences to engineering and physics, whenever temporal delays are important. In abstract terms, functional differential equations describe dynamical systems, when their evolution depends on the solution at prior times.
The central theme of this project is to forge strong links between the abstract theory of delay differential equations and practical aspects of epidemiology. Our research will combine competencies in different fields of mathematics and embrace theoretical issues as well as real life applications.
In particular, the theory of equations with state dependent delays is extremely challenging, and this field is at present on the verge of a breakthrough. Developing new theories in this area and connecting them to relevant applications would go far beyond the current research frontier of mathematical epidemiology and could open a new chapter in disease modeling.
Max ERC Funding
796 800 €
Duration
Start date: 2011-05-01, End date: 2016-12-31
Project acronym isoineqintgeo
Project Isoperimetric Inequalities and Integral Geometry
Researcher (PI) Franz Ewald Schuster
Host Institution (HI) TECHNISCHE UNIVERSITAET WIEN
Call Details Starting Grant (StG), PE1, ERC-2012-StG_20111012
Summary "Among several trends in convex geometric analysis, two have undergone an explosive development in recent years: the theory of affine isoperimetric and analytic inequalities, and the enhanced understanding of fundamental concepts of the subject as a whole lent by the theory of valuations. The proposal concerns both of these trends.
The connections between convex body valued valuations and isoperimetric inequalities (like, the Petty projection inequality or affine Sobolev inequalities and their Lp extensions) have attracted the interest of first-rate research groups in the world. However, the underlying bigger picture behind these strong relations has yet to be discovered. A goal of the proposed research program is to systematically exploit the ""valuations point of view"" to reshape not only the way (affine) isoperimetric inequalities are thought of and applied but also the way these powerful inequalities are established.
Through the introduction of new algebraic structures on the space of translation invariant scalar valued valuations substantial inroads have been made towards a fuller understanding of the integral geometry of groups acting transitively on the sphere. An aim of the proposed program is to introduce a corresponding algebraic machinery in the theory of convex body valued valuations which would provide the means to attack long standing major open problems in the area of affine isoperimetric inequalities.
It is the PI's strong belief that over the next years it will become clear that many classical inequalities from affine geometry hold in a much more general setting than is currently understood. This will not only lead to the discovery of new inequalities but also should reveal the full strength of affine inequalities compared to their counterparts from Euclidean geometry. The proposed research goals of this ERC grant proposal would therefore represent a huge step towards advancing these developments that will alter two main subjects at the same time."
Summary
"Among several trends in convex geometric analysis, two have undergone an explosive development in recent years: the theory of affine isoperimetric and analytic inequalities, and the enhanced understanding of fundamental concepts of the subject as a whole lent by the theory of valuations. The proposal concerns both of these trends.
The connections between convex body valued valuations and isoperimetric inequalities (like, the Petty projection inequality or affine Sobolev inequalities and their Lp extensions) have attracted the interest of first-rate research groups in the world. However, the underlying bigger picture behind these strong relations has yet to be discovered. A goal of the proposed research program is to systematically exploit the ""valuations point of view"" to reshape not only the way (affine) isoperimetric inequalities are thought of and applied but also the way these powerful inequalities are established.
Through the introduction of new algebraic structures on the space of translation invariant scalar valued valuations substantial inroads have been made towards a fuller understanding of the integral geometry of groups acting transitively on the sphere. An aim of the proposed program is to introduce a corresponding algebraic machinery in the theory of convex body valued valuations which would provide the means to attack long standing major open problems in the area of affine isoperimetric inequalities.
It is the PI's strong belief that over the next years it will become clear that many classical inequalities from affine geometry hold in a much more general setting than is currently understood. This will not only lead to the discovery of new inequalities but also should reveal the full strength of affine inequalities compared to their counterparts from Euclidean geometry. The proposed research goals of this ERC grant proposal would therefore represent a huge step towards advancing these developments that will alter two main subjects at the same time."
Max ERC Funding
982 461 €
Duration
Start date: 2012-11-01, End date: 2017-10-31
Project acronym MGUS screening RCT
Project Screening for monoclonal gammopathy of undetermined significance: A population-based randomized clinical trial
Researcher (PI) Sigurdur Yngvi KRISTINSSON
Host Institution (HI) HASKOLI ISLANDS
Call Details Starting Grant (StG), LS7, ERC-2016-STG
Summary Monoclonal gammopathy of undetermined significance (MGUS) is a very common precursor condition to multiple myeloma (MM), and related diseases, and can be found in approximately 4-5% of individuals over the age of 50 years. MM is always preceded by MGUS. Current risk stratification schemes, designed to predict those that will progress, are based on retrospective data and rely almost solely on serum protein markers. While they can differentiate high and low-risk patients, they cannot predict outcome for individual patients, are not integrated with one another, and have limited biological correlation. Based on retrospective data, it is recommended that individuals with MGUS are followed indefinitely; however no prospective study has ever been performed to evaluate this or identify optimal monitoring in MGUS individuals. We recently showed that MM patients with a prior knowledge of MGUS had superior survival compared to MM patients without, which raises the question whether routine screening for MGUS in the population might improve survival. To evaluate the impact of screening for MGUS on overall survival, to provide evidence for the optimal MGUS follow-up, and to integrate biological, imaging, and germline genetic markers in evaluating individual risk of progression, we propose to invite all individuals >50 years in Iceland (N=104,000) to participate in a screening study for MGUS. This will be done by utilizing already present infrastructure for screening in Iceland and the fact that most individuals >50 years have their blood drawn for various reasons during 3 years. We plan to perform electrophoresis and free light chain analyses in these individuals to diagnose MGUS. Individuals with MGUS will be invited to be included in a randomized clinical trial with 3 different arms to identify the optimal work-up and follow-up strategy and to build a new risk model for progression. Our large, unique, population-based study has major clinical and scientific implications.
Summary
Monoclonal gammopathy of undetermined significance (MGUS) is a very common precursor condition to multiple myeloma (MM), and related diseases, and can be found in approximately 4-5% of individuals over the age of 50 years. MM is always preceded by MGUS. Current risk stratification schemes, designed to predict those that will progress, are based on retrospective data and rely almost solely on serum protein markers. While they can differentiate high and low-risk patients, they cannot predict outcome for individual patients, are not integrated with one another, and have limited biological correlation. Based on retrospective data, it is recommended that individuals with MGUS are followed indefinitely; however no prospective study has ever been performed to evaluate this or identify optimal monitoring in MGUS individuals. We recently showed that MM patients with a prior knowledge of MGUS had superior survival compared to MM patients without, which raises the question whether routine screening for MGUS in the population might improve survival. To evaluate the impact of screening for MGUS on overall survival, to provide evidence for the optimal MGUS follow-up, and to integrate biological, imaging, and germline genetic markers in evaluating individual risk of progression, we propose to invite all individuals >50 years in Iceland (N=104,000) to participate in a screening study for MGUS. This will be done by utilizing already present infrastructure for screening in Iceland and the fact that most individuals >50 years have their blood drawn for various reasons during 3 years. We plan to perform electrophoresis and free light chain analyses in these individuals to diagnose MGUS. Individuals with MGUS will be invited to be included in a randomized clinical trial with 3 different arms to identify the optimal work-up and follow-up strategy and to build a new risk model for progression. Our large, unique, population-based study has major clinical and scientific implications.
Max ERC Funding
1 474 304 €
Duration
Start date: 2017-02-01, End date: 2022-01-31
Project acronym ONCOMECHAML
Project Common Oncogenic Mechanisms in Multi-Partner Translocation Families in Acute Myeloid Leukemia
Researcher (PI) Florian Grebien
Host Institution (HI) VETERINAERMEDIZINISCHE UNIVERSITAET WIEN
Call Details Starting Grant (StG), LS7, ERC-2014-STG
Summary Acute Myeloid Leukemia (AML) is the most frequent cancer of the blood system, with >80% mortality within 5 years of diagnosis. Straightforward clinical decisions are complicated by the genetic complexity of AML. In particular, fusion proteins arising from chromosomal aberrations are recurrently found in AML and often act as strong driver oncogenes. In “Multi-Partner Translocation” (MPT) families, one specific gene is fused to many recipient loci. Due to this modular architecture, MPT families are of particular interest to comparative studies of oncogenic mechanisms. The three most common MPT families in AML represent translocations of the MLL, RUNX1 and NUP98 genes. Despite their clinical significance, the molecular mechanism of transformation remains unknown for the majority of fusion proteins and it is unclear if transforming mechanisms are conserved within and across different MPT families.
We hypothesize that common oncogenic mechanisms of fusion proteins are encoded in physical and genetic cellular interaction networks that are specific to MPT families. We propose to delineate critical common effectors of oncogenic mechanisms in AML driven by MPT families through a comprehensive, comparative, functional analysis of 20 clinically representative MLL-, RUNX1- and NUP98-fusion proteins using a unique experimental pipeline. Characterization of protein interactomes and their effects on gene expression will identify common cellular denominators of MPT families, whose functional contribution will be assessed through pooled shRNA screens in clinically relevant model systems. High-confidence hits will be validated in mouse models and primary cells from AML patients. This project will generate large informative datasets and novel experimental systems that are of relevance for basic and clinical cancer research. It will contribute to improved understanding of oncogenic mechanisms, which may directly impact on diagnostic and therapeutic strategies in the management of AML.
Summary
Acute Myeloid Leukemia (AML) is the most frequent cancer of the blood system, with >80% mortality within 5 years of diagnosis. Straightforward clinical decisions are complicated by the genetic complexity of AML. In particular, fusion proteins arising from chromosomal aberrations are recurrently found in AML and often act as strong driver oncogenes. In “Multi-Partner Translocation” (MPT) families, one specific gene is fused to many recipient loci. Due to this modular architecture, MPT families are of particular interest to comparative studies of oncogenic mechanisms. The three most common MPT families in AML represent translocations of the MLL, RUNX1 and NUP98 genes. Despite their clinical significance, the molecular mechanism of transformation remains unknown for the majority of fusion proteins and it is unclear if transforming mechanisms are conserved within and across different MPT families.
We hypothesize that common oncogenic mechanisms of fusion proteins are encoded in physical and genetic cellular interaction networks that are specific to MPT families. We propose to delineate critical common effectors of oncogenic mechanisms in AML driven by MPT families through a comprehensive, comparative, functional analysis of 20 clinically representative MLL-, RUNX1- and NUP98-fusion proteins using a unique experimental pipeline. Characterization of protein interactomes and their effects on gene expression will identify common cellular denominators of MPT families, whose functional contribution will be assessed through pooled shRNA screens in clinically relevant model systems. High-confidence hits will be validated in mouse models and primary cells from AML patients. This project will generate large informative datasets and novel experimental systems that are of relevance for basic and clinical cancer research. It will contribute to improved understanding of oncogenic mechanisms, which may directly impact on diagnostic and therapeutic strategies in the management of AML.
Max ERC Funding
1 499 500 €
Duration
Start date: 2015-06-01, End date: 2020-05-31
Project acronym OPTIMALZ
Project Optical imaging of ocular pathology in Alzheimer’s disease
Researcher (PI) Bernhard Baumann
Host Institution (HI) MEDIZINISCHE UNIVERSITAET WIEN
Call Details Starting Grant (StG), LS7, ERC-2014-STG
Summary Novel diagnostic techniques and disease models have the powerful potential to provide new insights into pathological and pathophysiological processes. Ocular manifestations of Alzheimer’s disease (AD) emerge as novel and attractive alternative to investigate disease progression in parallel to the brain. Using the eye as a window to the brain, we propose to develop multi-functional optical coherence tomography (OCT) as a noninvasive in-vivo technique for preclinical imaging of AD pathology. OCT is analogous to ultrasound B-mode imaging, using light rather than acoustical waves, and performs high-resolution real time 3D imaging of microstructure in biological tissues in situ. Based on the optical polarization properties or movement of particles, functional OCT methods provide additional contrast channels. In the proposed project, we will unite/join standard and functional OCT for imaging ocular and cerebral pathology in AD mouse models with threefold contrast. Structural changes caused by neuronal cell loss in the retina will be assessed longitudinally and with micron-scale resolution. Beta-amyloid plaques are birefringent and are deposited in both brain and retina in AD. We propose to exploit these intrinsic polarization properties for noninvasive detection and longitudinal characterization/assessment of retinal plaque load. Simultaneously, we will assess AD-related changes in retinal microvasculature. Retinal blood flow will be measured in quantitative units and monitored during disease progression. In addition to the retina, we will perform longitudinal imaging of AD-related lesions in the ocular lens with OCT. By correlating ocular AD pathology as imaged with OCT to cerebral lesions, the proposed research provides a new set of in vivo parameters that potentially shed new light on the pathogenesis and impact early diagnosis of AD in aging populations worldwide.
Summary
Novel diagnostic techniques and disease models have the powerful potential to provide new insights into pathological and pathophysiological processes. Ocular manifestations of Alzheimer’s disease (AD) emerge as novel and attractive alternative to investigate disease progression in parallel to the brain. Using the eye as a window to the brain, we propose to develop multi-functional optical coherence tomography (OCT) as a noninvasive in-vivo technique for preclinical imaging of AD pathology. OCT is analogous to ultrasound B-mode imaging, using light rather than acoustical waves, and performs high-resolution real time 3D imaging of microstructure in biological tissues in situ. Based on the optical polarization properties or movement of particles, functional OCT methods provide additional contrast channels. In the proposed project, we will unite/join standard and functional OCT for imaging ocular and cerebral pathology in AD mouse models with threefold contrast. Structural changes caused by neuronal cell loss in the retina will be assessed longitudinally and with micron-scale resolution. Beta-amyloid plaques are birefringent and are deposited in both brain and retina in AD. We propose to exploit these intrinsic polarization properties for noninvasive detection and longitudinal characterization/assessment of retinal plaque load. Simultaneously, we will assess AD-related changes in retinal microvasculature. Retinal blood flow will be measured in quantitative units and monitored during disease progression. In addition to the retina, we will perform longitudinal imaging of AD-related lesions in the ocular lens with OCT. By correlating ocular AD pathology as imaged with OCT to cerebral lesions, the proposed research provides a new set of in vivo parameters that potentially shed new light on the pathogenesis and impact early diagnosis of AD in aging populations worldwide.
Max ERC Funding
1 497 000 €
Duration
Start date: 2015-09-01, End date: 2020-08-31
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
