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 ACTIVATION OF XCI
Project Molecular mechanisms controlling X chromosome inactivation
Researcher (PI) Joost Henk Gribnau
Host Institution (HI) ERASMUS UNIVERSITAIR MEDISCH CENTRUM ROTTERDAM
Call Details Starting Grant (StG), LS2, ERC-2010-StG_20091118
Summary In mammals, gene dosage of X-chromosomal genes is equalized between sexes by random inactivation of either one of the two X chromosomes in female cells. In the initial phase of X chromosome inactivation (XCI), a counting and initiation process determines the number of X chromosomes per nucleus, and elects the future inactive X chromosome (Xi). Xist is an X-encoded gene that plays a crucial role in the XCI process. At the start of XCI Xist expression is up-regulated and Xist RNA accumulates on the future Xi thereby initiating silencing in cis. Recent work performed in my laboratory indicates that the counting and initiation process is directed by a stochastic mechanism, in which each X chromosome has an independent probability to be inactivated. We also found that this probability is determined by the X:ploïdy ratio. These results indicated the presence of at least one X-linked activator of XCI. With a BAC screen we recently identified X-encoded RNF12 to be a dose-dependent activator of XCI. Expression of RNF12 correlates with Xist expression, and a heterozygous deletion of Rnf12 results in a marked loss of XCI in female cells. The presence of a small proportion of cells that still initiate XCI, in Rnf12+/- cells, also indicated that more XCI-activators are involved in XCI. Here, we propose to investigate the molecular mechanism by which RNF12 activates XCI in mouse and human, and to search for additional XCI-activators. We will also attempt to establish the role of different inhibitors of XCI, including CTCF and the pluripotency factors OCT4, SOX2 and NANOG. We anticipate that these studies will significantly advance our understanding of XCI mechanisms, which is highly relevant for a better insight in the manifestation of X-linked diseases that are affected by XCI.
Summary
In mammals, gene dosage of X-chromosomal genes is equalized between sexes by random inactivation of either one of the two X chromosomes in female cells. In the initial phase of X chromosome inactivation (XCI), a counting and initiation process determines the number of X chromosomes per nucleus, and elects the future inactive X chromosome (Xi). Xist is an X-encoded gene that plays a crucial role in the XCI process. At the start of XCI Xist expression is up-regulated and Xist RNA accumulates on the future Xi thereby initiating silencing in cis. Recent work performed in my laboratory indicates that the counting and initiation process is directed by a stochastic mechanism, in which each X chromosome has an independent probability to be inactivated. We also found that this probability is determined by the X:ploïdy ratio. These results indicated the presence of at least one X-linked activator of XCI. With a BAC screen we recently identified X-encoded RNF12 to be a dose-dependent activator of XCI. Expression of RNF12 correlates with Xist expression, and a heterozygous deletion of Rnf12 results in a marked loss of XCI in female cells. The presence of a small proportion of cells that still initiate XCI, in Rnf12+/- cells, also indicated that more XCI-activators are involved in XCI. Here, we propose to investigate the molecular mechanism by which RNF12 activates XCI in mouse and human, and to search for additional XCI-activators. We will also attempt to establish the role of different inhibitors of XCI, including CTCF and the pluripotency factors OCT4, SOX2 and NANOG. We anticipate that these studies will significantly advance our understanding of XCI mechanisms, which is highly relevant for a better insight in the manifestation of X-linked diseases that are affected by XCI.
Max ERC Funding
1 500 000 €
Duration
Start date: 2011-04-01, End date: 2016-03-31
Project acronym ANOREP
Project Targeting the reproductive biology of the malaria mosquito Anopheles gambiae: from laboratory studies to field applications
Researcher (PI) Flaminia Catteruccia
Host Institution (HI) UNIVERSITA DEGLI STUDI DI PERUGIA
Call Details Starting Grant (StG), LS2, ERC-2010-StG_20091118
Summary Anopheles gambiae mosquitoes are the major vectors of malaria, a disease with devastating consequences for
human health. Novel methods for controlling the natural vector populations are urgently needed, given the
evolution of insecticide resistance in mosquitoes and the lack of novel insecticidals. Understanding the
processes at the bases of mosquito biology may help to roll back malaria. In this proposal, we will target
mosquito reproduction, a major determinant of the An. gambiae vectorial capacity. This will be achieved at
two levels: (i) fundamental research, to provide a deeper knowledge of the processes regulating reproduction
in this species, and (ii) applied research, to identify novel targets and to develop innovative approaches for
the control of natural populations. We will focus our analysis on three major players of mosquito
reproduction: male accessory glands (MAGs), sperm, and spermatheca, in both laboratory and field settings.
We will then translate this information into the identification of inhibitors of mosquito fertility. The
experimental activities will be divided across three objectives. In Objective 1, we will unravel the role of the
MAGs in shaping mosquito fertility and behaviour, by performing a combination of transcriptional and
functional studies that will reveal the multifaceted activities of these tissues. In Objective 2 we will instead
focus on the identification of the male and female factors responsible for sperm viability and function.
Results obtained in both objectives will be validated in field mosquitoes. In Objective 3, we will perform
screens aimed at the identification of inhibitors of mosquito reproductive success. This study will reveal as
yet unknown molecular mechanisms underlying reproductive success in mosquitoes, considerably increasing
our knowledge beyond the state-of-the-art and critically contributing with innovative tools and ideas to the
fight against malaria.
Summary
Anopheles gambiae mosquitoes are the major vectors of malaria, a disease with devastating consequences for
human health. Novel methods for controlling the natural vector populations are urgently needed, given the
evolution of insecticide resistance in mosquitoes and the lack of novel insecticidals. Understanding the
processes at the bases of mosquito biology may help to roll back malaria. In this proposal, we will target
mosquito reproduction, a major determinant of the An. gambiae vectorial capacity. This will be achieved at
two levels: (i) fundamental research, to provide a deeper knowledge of the processes regulating reproduction
in this species, and (ii) applied research, to identify novel targets and to develop innovative approaches for
the control of natural populations. We will focus our analysis on three major players of mosquito
reproduction: male accessory glands (MAGs), sperm, and spermatheca, in both laboratory and field settings.
We will then translate this information into the identification of inhibitors of mosquito fertility. The
experimental activities will be divided across three objectives. In Objective 1, we will unravel the role of the
MAGs in shaping mosquito fertility and behaviour, by performing a combination of transcriptional and
functional studies that will reveal the multifaceted activities of these tissues. In Objective 2 we will instead
focus on the identification of the male and female factors responsible for sperm viability and function.
Results obtained in both objectives will be validated in field mosquitoes. In Objective 3, we will perform
screens aimed at the identification of inhibitors of mosquito reproductive success. This study will reveal as
yet unknown molecular mechanisms underlying reproductive success in mosquitoes, considerably increasing
our knowledge beyond the state-of-the-art and critically contributing with innovative tools and ideas to the
fight against malaria.
Max ERC Funding
1 500 000 €
Duration
Start date: 2011-01-01, End date: 2015-12-31
Project acronym CBCD
Project Understanding the basis of cerebellar and brainstem congenital defects: from clinical and molecular characterisation to the development of a novel neuroembryonic in vitro model
Researcher (PI) Enza Maria Valente
Host Institution (HI) FONDAZIONE SANTA LUCIA
Call Details Starting Grant (StG), LS7, ERC-2010-StG_20091118
Summary Cerebellar and brainstem congenital defects (CBCDs) are heterogeneous disorders with high pre-and post-natal mortality and morbidity. Their genetic basis and pathogenetic mechanisms are largely unknown, hampering patients’ diagnosis and management and family counselling. This project aims at improve current understanding of primary CBCDs through a multidisciplinary approach combining innovative clinical, neuroimaging, molecular and functional studies, that will be articulated in four workpackages:
WP1- Clinical and neuroimaging studies: collection of detailed data and biological samples from a large cohort of patients covering a broad spectrum of CBCDs, neuroimaging classification based on magnetic resonance imaging and tractography, genotype-phenotype correlates and follow-up studies.
WP2 - Molecular studies on mendelian CBCDs: high-throughput resequencing of ciliary genes to identify pathogenic mutations and genetic modifiers in patients with ciliopathies, identification of novel disease genes, mutation analysis of genes causative of other mendelian CBCDs.
WP3 - Molecular studies on sporadic CBCDs: identification of cryptic chromosomal rearrangements by high resolution SNP-array analysis, selection and mutation analysis of candidate genes mapping to the rearranged regions.
WP4 - Functional studies: optimisation of a novel neuroembryonic in vitro model derived from mouse embryonic stem cells, to test the role of known and candidate disease genes (from WP2 and 3) on cerebellar and brainstem development, define the pathways in which they are involved and the effect of disease-causative mutations.
This project is expected to improve the current CBCD nosology, identify novel genes and mechanisms involved in cerebellar and brainstem development that are responsible for mendelian or sporadic defects, expand the available tools for pre- and post-natal diagnosis and identify clinical-genetic correlates and prognostic indexes.
Summary
Cerebellar and brainstem congenital defects (CBCDs) are heterogeneous disorders with high pre-and post-natal mortality and morbidity. Their genetic basis and pathogenetic mechanisms are largely unknown, hampering patients’ diagnosis and management and family counselling. This project aims at improve current understanding of primary CBCDs through a multidisciplinary approach combining innovative clinical, neuroimaging, molecular and functional studies, that will be articulated in four workpackages:
WP1- Clinical and neuroimaging studies: collection of detailed data and biological samples from a large cohort of patients covering a broad spectrum of CBCDs, neuroimaging classification based on magnetic resonance imaging and tractography, genotype-phenotype correlates and follow-up studies.
WP2 - Molecular studies on mendelian CBCDs: high-throughput resequencing of ciliary genes to identify pathogenic mutations and genetic modifiers in patients with ciliopathies, identification of novel disease genes, mutation analysis of genes causative of other mendelian CBCDs.
WP3 - Molecular studies on sporadic CBCDs: identification of cryptic chromosomal rearrangements by high resolution SNP-array analysis, selection and mutation analysis of candidate genes mapping to the rearranged regions.
WP4 - Functional studies: optimisation of a novel neuroembryonic in vitro model derived from mouse embryonic stem cells, to test the role of known and candidate disease genes (from WP2 and 3) on cerebellar and brainstem development, define the pathways in which they are involved and the effect of disease-causative mutations.
This project is expected to improve the current CBCD nosology, identify novel genes and mechanisms involved in cerebellar and brainstem development that are responsible for mendelian or sporadic defects, expand the available tools for pre- and post-natal diagnosis and identify clinical-genetic correlates and prognostic indexes.
Max ERC Funding
1 367 960 €
Duration
Start date: 2011-08-01, End date: 2018-03-31
Project acronym CGT HEMOPHILIA A
Project Cell and gene therapy based strategies to correct the bleeding phenotype in Hemophilia A
Researcher (PI) Antonia Follenzi
Host Institution (HI) UNIVERSITA DEGLI STUDI DEL PIEMONTE ORIENTALE AMEDEO AVOGADRO
Call Details Starting Grant (StG), LS7, ERC-2010-StG_20091118
Summary Currently, haemophilia A cannot be cured. To prevent major bleeding episodes in haemophilia, human Factor VIII (FVIII) protein must be frequently administered as prophylaxis or on demand. This treatment is complicated by its high cost and development of antibodies that neutralize FVIII activity in 20 to 30% of the patients. Therefore, permanent solutions in the form of cell and gene therapy are very attractive for haemophilia A. Recently, we demonstrated in a murine model that liver sinusoidal endothelial cells (LSEC) produce and secrete FVIII, although not exclusively. We have also found that these mice can be treated by reconstitution with wild-type bone marrow, indicating that bone marrow-derived cells, of hematopoietic, mesenchymal or even endothelial origin, can produce and secrete FVIII. Based on these findings in mice, I propose that human LSEC, umbilical cord blood cells, and bone marrow cells might be suitable sources of FVIII to be used for cell replacement therapy for haemophilia A. To advance opportunities for cell and gene therapies in haemophilia A and for identifying additional cell sources of FVIII, I intend to explore whether replacement of liver endothelium and bone marrow in immnocompromised Haemophilia A mice with healthy human cells will provide therapeutic correction. Recently, the possibility of reprogramming mature somatic cells to generate induced pluripotent stem (iPS) cells has enabled the derivation of disease-specific pluripotent cells, thus providing unprecedented experimental platforms to treat human diseases. Therefore, I intend to study whether the generation of patient-specific iPS cells may be applied to cell and gene therapy of coagulation disorders and in particular for the treatment of Haemophilia A. Studies with these novel target cells may impact significantly the future course of Haemophilia A by providing proof-of feasibility of a novel therapy strategies.
Summary
Currently, haemophilia A cannot be cured. To prevent major bleeding episodes in haemophilia, human Factor VIII (FVIII) protein must be frequently administered as prophylaxis or on demand. This treatment is complicated by its high cost and development of antibodies that neutralize FVIII activity in 20 to 30% of the patients. Therefore, permanent solutions in the form of cell and gene therapy are very attractive for haemophilia A. Recently, we demonstrated in a murine model that liver sinusoidal endothelial cells (LSEC) produce and secrete FVIII, although not exclusively. We have also found that these mice can be treated by reconstitution with wild-type bone marrow, indicating that bone marrow-derived cells, of hematopoietic, mesenchymal or even endothelial origin, can produce and secrete FVIII. Based on these findings in mice, I propose that human LSEC, umbilical cord blood cells, and bone marrow cells might be suitable sources of FVIII to be used for cell replacement therapy for haemophilia A. To advance opportunities for cell and gene therapies in haemophilia A and for identifying additional cell sources of FVIII, I intend to explore whether replacement of liver endothelium and bone marrow in immnocompromised Haemophilia A mice with healthy human cells will provide therapeutic correction. Recently, the possibility of reprogramming mature somatic cells to generate induced pluripotent stem (iPS) cells has enabled the derivation of disease-specific pluripotent cells, thus providing unprecedented experimental platforms to treat human diseases. Therefore, I intend to study whether the generation of patient-specific iPS cells may be applied to cell and gene therapy of coagulation disorders and in particular for the treatment of Haemophilia A. Studies with these novel target cells may impact significantly the future course of Haemophilia A by providing proof-of feasibility of a novel therapy strategies.
Max ERC Funding
1 123 000 €
Duration
Start date: 2011-05-01, End date: 2017-04-30
Project acronym EARLYWARNING
Project Generic Early Warning Signals for Critical Transitions
Researcher (PI) Marten Scheffer
Host Institution (HI) WAGENINGEN UNIVERSITY
Call Details Advanced Grant (AdG), LS8, ERC-2010-AdG_20100317
Summary Abrupt shifts occasionally reshape complex systems in nature ranging in scale from lakes and reefs to regional climate systems. Such shifts sometimes represent critical transitions in the sense that they happen at tipping points where runaway change propels the system towards an alterative contrasting state. Although the mechanism of critical transitions can often be reconstructed in the hindsight, we are virtually unable to predict when they will happen in advance. Simulation models for complex environmental systems are simply not good enough to predict tipping points, and there is little hope that this will change over the coming decades. The proposed project is aimed at developing an alternative way to predict critical transitions. We aim at finding early warning signals for such transitions that are generic in the sense that they work irrespective of the (often poorly known) mechanisms responsible for the tipping points. Mathematical theory indicates that this might be possible. However, although excitement about these ideas is emerging, we are far from having a cohesive theory, let alone practical approaches for predicting critical transitions in large complex systems like lakes, coral reefs or the climate. I will work towards this goal with my team along three lines: 1) Develop a comprehensive theory of early warning signals using analytical mathematical techniques as well as models ranging in character from simple and transparent to elaborate and realistic; 2) Test the theory on experimental plankton systems kept in controlled microcosms; and 3) Analyze data from real systems that go through catastrophic transitions. The anticipated results would imply a major breakthrough in a field of research that is exiting as well as highly relevant to society. If we are successful, it would allow us to anticipate critical transitions even in large complex systems where we have little hope of predicting tipping points on the basis of mechanistic models.
Summary
Abrupt shifts occasionally reshape complex systems in nature ranging in scale from lakes and reefs to regional climate systems. Such shifts sometimes represent critical transitions in the sense that they happen at tipping points where runaway change propels the system towards an alterative contrasting state. Although the mechanism of critical transitions can often be reconstructed in the hindsight, we are virtually unable to predict when they will happen in advance. Simulation models for complex environmental systems are simply not good enough to predict tipping points, and there is little hope that this will change over the coming decades. The proposed project is aimed at developing an alternative way to predict critical transitions. We aim at finding early warning signals for such transitions that are generic in the sense that they work irrespective of the (often poorly known) mechanisms responsible for the tipping points. Mathematical theory indicates that this might be possible. However, although excitement about these ideas is emerging, we are far from having a cohesive theory, let alone practical approaches for predicting critical transitions in large complex systems like lakes, coral reefs or the climate. I will work towards this goal with my team along three lines: 1) Develop a comprehensive theory of early warning signals using analytical mathematical techniques as well as models ranging in character from simple and transparent to elaborate and realistic; 2) Test the theory on experimental plankton systems kept in controlled microcosms; and 3) Analyze data from real systems that go through catastrophic transitions. The anticipated results would imply a major breakthrough in a field of research that is exiting as well as highly relevant to society. If we are successful, it would allow us to anticipate critical transitions even in large complex systems where we have little hope of predicting tipping points on the basis of mechanistic models.
Max ERC Funding
2 299 171 €
Duration
Start date: 2011-06-01, End date: 2016-05-31
Project acronym ENCODING IN AXONS
Project Identifying mechanisms of information encoding in myelinated single axons
Researcher (PI) Maarten Kole
Host Institution (HI) KONINKLIJKE NEDERLANDSE AKADEMIE VAN WETENSCHAPPEN - KNAW
Call Details Starting Grant (StG), LS5, ERC-2010-StG_20091118
Summary A major challenge in neuroscience is to understand how information is stored and coded within single nerve cells (neurons) and across neuron populations in the brain. Nerve cell fibres (axons) are thought to provide the wiring to connect neurons and conduct the electrical nerve impulse (action potential; AP). Recent discoveries, however, show that the initial part of axons actively participates in modulating APs and providing a means to enhance the computational repertoire of neurons in the central nervous system. To decrease the temporal delay in information transmission over long distances most axons are myelinated. Here, we will test the hypothesis that the degree of myelination of single axons directly and indirectly influences the mechanisms of AP generation and neural coding. We will use a novel approach of patch-clamp recording combined with immunohistochemical and ultrastructural identification to develop a detailed model of single myelinated neocortical axons. We also will investigate the neuron-glia interactions responsible for the myelination process and measure whether their development follows an activity-dependent process. Finally, we will elucidate the physiological and molecular similarities and discrepancies between myelinated and experimentally demyelinated single neocortical axons. These studies will provide a novel methodological framework to study central nervous system axons and yield basic insights into myelin physiology and pathophysiology.
Summary
A major challenge in neuroscience is to understand how information is stored and coded within single nerve cells (neurons) and across neuron populations in the brain. Nerve cell fibres (axons) are thought to provide the wiring to connect neurons and conduct the electrical nerve impulse (action potential; AP). Recent discoveries, however, show that the initial part of axons actively participates in modulating APs and providing a means to enhance the computational repertoire of neurons in the central nervous system. To decrease the temporal delay in information transmission over long distances most axons are myelinated. Here, we will test the hypothesis that the degree of myelination of single axons directly and indirectly influences the mechanisms of AP generation and neural coding. We will use a novel approach of patch-clamp recording combined with immunohistochemical and ultrastructural identification to develop a detailed model of single myelinated neocortical axons. We also will investigate the neuron-glia interactions responsible for the myelination process and measure whether their development follows an activity-dependent process. Finally, we will elucidate the physiological and molecular similarities and discrepancies between myelinated and experimentally demyelinated single neocortical axons. These studies will provide a novel methodological framework to study central nervous system axons and yield basic insights into myelin physiology and pathophysiology.
Max ERC Funding
1 994 640 €
Duration
Start date: 2011-04-01, End date: 2016-03-31
Project acronym FLARE
Project Floral Integrating Networks at the Shoot Apical Meristem of Rice
Researcher (PI) Fabio Fornara
Host Institution (HI) UNIVERSITA DEGLI STUDI DI MILANO
Call Details Starting Grant (StG), LS9, ERC-2010-StG_20091118
Summary Discriminating differences in day length is critical for many organisms to synchronize reproduction with the most favourable season of the year. Plants have evolved sophisticated time-keeping mechanisms that largely work in leaves, to measure the duration of the day. Upon perception of favourable day lengths, a leaf-borne signal moves to the shoot apical meristem to induce flower formation. Rice is a crop whose yield heavily depends on flowering at the right time, and genetic variation within leaf regulators contributes to diversification of flowering responses among different rice varieties. However, how the shoot apical meristem responds to changes in day length and initiates flowering is currently unknown. High-yielding European rice varieties flower within a limited range of days and expanding such range would prove beneficial to increase yield and expand cultivation to different environments. Our goal is to identify novel genes that modify meristem sensitivity to day length, and breed them into high-yielding cultivars. Together with the gene pool controlling day length responses in the leaves, these novel alleles will allow to design varieties with diverse sensitivities to photoperiod and will distribute the reproductive phase over a broader period of time. This knowledge-based breeding will require preliminary studies in order to identify regulators acting in the shoot apical meristem. To this extent, rice provides an excellent biological model for the availability of powerful genetic and molecular tools. I am proposing a number of genetic and biochemical screens that will allow us to explore the rice genome for genes required at the shoot apical meristem to drive reproductive phase transitions. We will investigate genetic variation in these components, relate it to flowering and adaptation, and use it for introgressing novel alleles into elite germplasm.
Summary
Discriminating differences in day length is critical for many organisms to synchronize reproduction with the most favourable season of the year. Plants have evolved sophisticated time-keeping mechanisms that largely work in leaves, to measure the duration of the day. Upon perception of favourable day lengths, a leaf-borne signal moves to the shoot apical meristem to induce flower formation. Rice is a crop whose yield heavily depends on flowering at the right time, and genetic variation within leaf regulators contributes to diversification of flowering responses among different rice varieties. However, how the shoot apical meristem responds to changes in day length and initiates flowering is currently unknown. High-yielding European rice varieties flower within a limited range of days and expanding such range would prove beneficial to increase yield and expand cultivation to different environments. Our goal is to identify novel genes that modify meristem sensitivity to day length, and breed them into high-yielding cultivars. Together with the gene pool controlling day length responses in the leaves, these novel alleles will allow to design varieties with diverse sensitivities to photoperiod and will distribute the reproductive phase over a broader period of time. This knowledge-based breeding will require preliminary studies in order to identify regulators acting in the shoot apical meristem. To this extent, rice provides an excellent biological model for the availability of powerful genetic and molecular tools. I am proposing a number of genetic and biochemical screens that will allow us to explore the rice genome for genes required at the shoot apical meristem to drive reproductive phase transitions. We will investigate genetic variation in these components, relate it to flowering and adaptation, and use it for introgressing novel alleles into elite germplasm.
Max ERC Funding
1 499 880 €
Duration
Start date: 2011-04-01, End date: 2016-03-31
Project acronym I-MIRNOME
Project Lymphocyte microRNAs in health and disease: Understanding lymphocyte functions through the identification of microRNA target genes and exploiting serum microRNA signatures to monitor immune responses
Researcher (PI) Sergio Abrignani
Host Institution (HI) UNIVERSITA DEGLI STUDI DI MILANO
Call Details Advanced Grant (AdG), LS7, ERC-2010-AdG_20100317
Summary Background: CD4+ T lymphocyte subsets orchestrate immune responses in health and disease. Little is known on control of T cell differentiation exerted by microRNA that affect mRNA translation. The identification of microRNA and their targets that regulate differentiation of T cell subsets may provide new therapeutic targets for immune-mediated diseases. Since microRNA are released in exosomes and circulate in blood, activities of tissue-derived lymphocytes could be assessed by microRNA signatures in the serum. We have defined microRNAs present in resting lymphocyte subsets from peripheral blood and measured lymphocyte-derived microRNAs in the serum. We have also solved important challenges for the identification of microRNA targets, the definition of signatures of activated T cells and their monitoring in the serum, which form the key topics of this application. Advancing State-of-the-Art and objectives: We will identify microRNA of CD4+ T cell subsets purified from inflamed organs and investigate microRNA target network that regulates T cell differentiation. We will exploit this knowledge to profile signatures of in vivo activated T cells and to map genes that could improve understanding of T cell commitment. We will also develop quantitative assays to monitor microRNA signatures in the serum and provide functional evidence of key genes targeted by microRNA which could be targets of immunomodulatory drugs. Significance: This application addresses important challenges at the frontiers of immunology and could lead to significant advances in immunotherapies and diagnostic tools for patients with immune mediated diseases. New ways of identifying microRNA targets and techniques to quantify microRNA signatures in the serum, could be widely applicable in biomedical research.
Summary
Background: CD4+ T lymphocyte subsets orchestrate immune responses in health and disease. Little is known on control of T cell differentiation exerted by microRNA that affect mRNA translation. The identification of microRNA and their targets that regulate differentiation of T cell subsets may provide new therapeutic targets for immune-mediated diseases. Since microRNA are released in exosomes and circulate in blood, activities of tissue-derived lymphocytes could be assessed by microRNA signatures in the serum. We have defined microRNAs present in resting lymphocyte subsets from peripheral blood and measured lymphocyte-derived microRNAs in the serum. We have also solved important challenges for the identification of microRNA targets, the definition of signatures of activated T cells and their monitoring in the serum, which form the key topics of this application. Advancing State-of-the-Art and objectives: We will identify microRNA of CD4+ T cell subsets purified from inflamed organs and investigate microRNA target network that regulates T cell differentiation. We will exploit this knowledge to profile signatures of in vivo activated T cells and to map genes that could improve understanding of T cell commitment. We will also develop quantitative assays to monitor microRNA signatures in the serum and provide functional evidence of key genes targeted by microRNA which could be targets of immunomodulatory drugs. Significance: This application addresses important challenges at the frontiers of immunology and could lead to significant advances in immunotherapies and diagnostic tools for patients with immune mediated diseases. New ways of identifying microRNA targets and techniques to quantify microRNA signatures in the serum, could be widely applicable in biomedical research.
Max ERC Funding
2 496 000 €
Duration
Start date: 2011-06-01, End date: 2016-05-31
Project acronym INTERIMPACT
Project Impact of identified interneurons on cellular network mechanisms in the human and rodent neocortex
Researcher (PI) Gábor Tamás
Host Institution (HI) Szegedi Tudomanyegyetem - Hungarian-Netherlands School of Educational Management
Call Details Advanced Grant (AdG), LS5, ERC-2010-AdG_20100317
Summary This application addresses mechanisms linking the activity of single neurons with network events by defining the function of identified cell types in the cerebral cortex. The key hypotheses emerged from our experiments and propose that neurogliaform cells and axo-axonic cells achieve their function in the cortex through extreme forms of unspecificity and specificity, respectively. The project capitalizes on our discovery that neurogliaform cells reach GABAA and GABAB receptors on target cells through unitary volume transmission going beyond the classical theory which states that single cortical neurons act in or around synaptic junctions. We propose that the spatial unspecificity of neurotransmitter action leads to unprecedented functional capabilities for a single neuron simultaneously acting on neuronal, glial and vascular components of the surrounding area allowing neurogliaform cells to synchronize metabolic demand and supply in microcircuits. In contrast, axo-axonic cells represent extreme spatial specificity in the brain: terminals of axo-axonic cells exclusively target the axon initial segment of pyramidal neurons. Axo-axonic cells were considered as the most potent inhibitory neurons of the cortex. However, our experiments suggested that axo-axonic cells can be the most powerful excitatory neurons known to date by triggering complex network events. Our unprecedented recordings in the human cortex show that axo-axonic cells are crucial in activating functional assemblies which were implicated in higher order cognitive representations. We aim to define interactions between active cortical networks and axo-axonic cell triggered assemblies with an emphasis on mechanisms modulated by neurogliaform cells and commonly prescribed drugs.
Summary
This application addresses mechanisms linking the activity of single neurons with network events by defining the function of identified cell types in the cerebral cortex. The key hypotheses emerged from our experiments and propose that neurogliaform cells and axo-axonic cells achieve their function in the cortex through extreme forms of unspecificity and specificity, respectively. The project capitalizes on our discovery that neurogliaform cells reach GABAA and GABAB receptors on target cells through unitary volume transmission going beyond the classical theory which states that single cortical neurons act in or around synaptic junctions. We propose that the spatial unspecificity of neurotransmitter action leads to unprecedented functional capabilities for a single neuron simultaneously acting on neuronal, glial and vascular components of the surrounding area allowing neurogliaform cells to synchronize metabolic demand and supply in microcircuits. In contrast, axo-axonic cells represent extreme spatial specificity in the brain: terminals of axo-axonic cells exclusively target the axon initial segment of pyramidal neurons. Axo-axonic cells were considered as the most potent inhibitory neurons of the cortex. However, our experiments suggested that axo-axonic cells can be the most powerful excitatory neurons known to date by triggering complex network events. Our unprecedented recordings in the human cortex show that axo-axonic cells are crucial in activating functional assemblies which were implicated in higher order cognitive representations. We aim to define interactions between active cortical networks and axo-axonic cell triggered assemblies with an emphasis on mechanisms modulated by neurogliaform cells and commonly prescribed drugs.
Max ERC Funding
2 391 695 €
Duration
Start date: 2011-06-01, End date: 2017-05-31
