Project acronym NextGen IO
Project Exploiting the hypoxia response in T cells for Next-Generation Immuno-Oncology
Researcher (PI) Francisco de Asis PALAZON GARCIA
Host Institution (HI) ASOCIACION CENTRO DE INVESTIGACION COOPERATIVA EN BIOCIENCIAS
Call Details Starting Grant (StG), LS7, ERC-2018-STG
Summary NextGen_IO has a core focus on immuno-oncology, specifically on target discovery and drug development, to exploit several opportunities that the hypoxia pathway in T cells offers for the treatment of cancer. It is well recognised that the clinical response of immunotherapies depends on the ability of T-cells to mount an effective effector response, persist in treated patients and avoid exhaustion and toxicities. Several approaches to immunotherapy have shown promise in clinical trials, especially the use of immune checkpoint inhibitors and, more recently, autologous adoptive T-cell therapies. However, current state-of-the-art immunotherapies are only effective in a small fraction of patients, offering a medical need to be addressed in several cancer types. Importantly, the tumor microenvironment has specific features that impact the immune response, including decreased oxygenation, aberrant vascularization and altered nutrient availability; all these influence the success of immunotherapies. During the last 10 years, my research has been focused on elucidating the role of the oxygen sensing machinery in T cell function, and the link of hypoxia-driven metabolism and epigenetic modifications with T cell differentiation into effector and memory T cells within the context of cancer immunotherapy. The current proposal aims to exploit these previous findings with a multi-disciplinary strategy, to deliver several early-stage drug discovery outputs.
The main objectives are:
1. Development of a novel small molecule inhibitor to modulate the hypoxic response in T cells.
2. Therapeutic target discovery in T cells, focused on hypoxia-driven epigenetic modifications.
3. Development of hypoxia-inducible molecular switches for adoptive T cell therapy.
Successful completion of the project will allow me to further innovate and consolidate my position as a leader in this field, harness this pathway for therapeutic potential and explore potential combinatorial approaches.
Summary
NextGen_IO has a core focus on immuno-oncology, specifically on target discovery and drug development, to exploit several opportunities that the hypoxia pathway in T cells offers for the treatment of cancer. It is well recognised that the clinical response of immunotherapies depends on the ability of T-cells to mount an effective effector response, persist in treated patients and avoid exhaustion and toxicities. Several approaches to immunotherapy have shown promise in clinical trials, especially the use of immune checkpoint inhibitors and, more recently, autologous adoptive T-cell therapies. However, current state-of-the-art immunotherapies are only effective in a small fraction of patients, offering a medical need to be addressed in several cancer types. Importantly, the tumor microenvironment has specific features that impact the immune response, including decreased oxygenation, aberrant vascularization and altered nutrient availability; all these influence the success of immunotherapies. During the last 10 years, my research has been focused on elucidating the role of the oxygen sensing machinery in T cell function, and the link of hypoxia-driven metabolism and epigenetic modifications with T cell differentiation into effector and memory T cells within the context of cancer immunotherapy. The current proposal aims to exploit these previous findings with a multi-disciplinary strategy, to deliver several early-stage drug discovery outputs.
The main objectives are:
1. Development of a novel small molecule inhibitor to modulate the hypoxic response in T cells.
2. Therapeutic target discovery in T cells, focused on hypoxia-driven epigenetic modifications.
3. Development of hypoxia-inducible molecular switches for adoptive T cell therapy.
Successful completion of the project will allow me to further innovate and consolidate my position as a leader in this field, harness this pathway for therapeutic potential and explore potential combinatorial approaches.
Max ERC Funding
1 993 575 €
Duration
Start date: 2019-02-01, End date: 2024-01-31
Project acronym NONCODEVOL
Project Evolutionary genomics of long, non-coding RNAs
Researcher (PI) Juan Antonio Gabaldón Estevan
Host Institution (HI) FUNDACIO CENTRE DE REGULACIO GENOMICA
Call Details Starting Grant (StG), LS2, ERC-2012-StG_20111109
Summary Recent genomics analyses have facilitated the discovery of a novel major class of stable transcripts, now called long non-coding RNAs (lncRNAs). A growing number of analyses have implicated lncRNAs in the regulation of gene expression, dosage compensation and imprinting, and there is increasing evidence suggesting the involvement of lncRNAs in various diseases such as cancer. Despite recent advances, however, the role of the large majority of lncRNAs remains unknown and there is current debate on what fraction of lncRNAs may just represent transcriptional noise. Moreover, despite a growing number of lncRNAs catalogues for diverse model species, we lack a proper understanding of how these molecules evolve across genomes. Evolutionary analyses of protein-coding genes have proved tremendously useful in elucidating functional relationships and in understanding how the processes in which they are involved are shaped during evolution. Similar insights may be expected from a proper evolutionary characterization of lncRNAs, although the lack of proper tools and basic knowledge of underlying evolutionary mechanisms are a sizable challenge. Here, I propose to combine state-of-the-art computational and sequencing techniques in order to elucidate what evolutionary mechanisms are shaping this enigmatic component of eukaryotic genomes.The first goal is to enable large-scale phylogenomic analyses of lncRNAs by developing, for these molecules, methodologies that are now standard in the evolutionary analysis of protein-coding genes. The second goal is to explore, at high levels of resolution, the evolutionary dynamics of lncRNAs across selected eukaryotic groups for which novel genome-wide data will be produced experimentally using recently developed sequencing techniques that enable obtaining genome-wide footprints of RNA secondary structure. Finally, this dataset will be used to test the impact on lncRNAs evolution of processes known to be important in protein-coding genes.
Summary
Recent genomics analyses have facilitated the discovery of a novel major class of stable transcripts, now called long non-coding RNAs (lncRNAs). A growing number of analyses have implicated lncRNAs in the regulation of gene expression, dosage compensation and imprinting, and there is increasing evidence suggesting the involvement of lncRNAs in various diseases such as cancer. Despite recent advances, however, the role of the large majority of lncRNAs remains unknown and there is current debate on what fraction of lncRNAs may just represent transcriptional noise. Moreover, despite a growing number of lncRNAs catalogues for diverse model species, we lack a proper understanding of how these molecules evolve across genomes. Evolutionary analyses of protein-coding genes have proved tremendously useful in elucidating functional relationships and in understanding how the processes in which they are involved are shaped during evolution. Similar insights may be expected from a proper evolutionary characterization of lncRNAs, although the lack of proper tools and basic knowledge of underlying evolutionary mechanisms are a sizable challenge. Here, I propose to combine state-of-the-art computational and sequencing techniques in order to elucidate what evolutionary mechanisms are shaping this enigmatic component of eukaryotic genomes.The first goal is to enable large-scale phylogenomic analyses of lncRNAs by developing, for these molecules, methodologies that are now standard in the evolutionary analysis of protein-coding genes. The second goal is to explore, at high levels of resolution, the evolutionary dynamics of lncRNAs across selected eukaryotic groups for which novel genome-wide data will be produced experimentally using recently developed sequencing techniques that enable obtaining genome-wide footprints of RNA secondary structure. Finally, this dataset will be used to test the impact on lncRNAs evolution of processes known to be important in protein-coding genes.
Max ERC Funding
1 302 113 €
Duration
Start date: 2013-01-01, End date: 2017-12-31
Project acronym NutrientSensingVivo
Project The Physiology of Nutrient Sensing by mTOR
Researcher (PI) Alejo Efeyan
Host Institution (HI) FUNDACION CENTRO NACIONAL DE INVESTIGACIONES ONCOLOGICAS CARLOS III
Call Details Starting Grant (StG), LS4, ERC-2014-STG
Summary A major role of metabolic alterations in the development of several human diseases, as diabetes, cancer and in the onset of ageing is becoming increasingly evident. This has a deep impact for human health due to the alarming increase in nutrient intake and obesity in the last decades. Fundamental aspects of how aberrant nutrient fluctuations trigger deregulated hormone levels and endocrine signals have been elucidated, being a prime example the phenomenon of insulin resistance. In contrast, how changes in nutrient levels elicit direct cell-autonomous signal transduction cascades and the consequences of these responses in physiology are less clear.
The signalling circuitry of direct nutrient sensing converges with that of hormones in the regulation of the mechanistic target of rapamycin (mTOR) kinase, a driver of anabolism, cell growth and proliferation. Deregulation of mTORC1 activity underlies the pathogenesis of cancer and diabetes, and its inhibitor rapamycin is approved as an anti-cancer agent and delays ageing from yeast to mammals. In spite of its importance for human disease, our understanding of the nutrient sensing signalling pathway and its impact in physiology is largely incomplete, as only a few years ago the direct molecular link between nutrients and mTORC1 activation, the Rag GTPases, were identified.
The present proposal aims to determine how the nutrient sensing signalling pathway affects mammalian physiology and metabolism, and whether its deregulation contributes to cancer, insulin resistance and aging. In particular, the objectives are: 1) To identify novel regulators of the Rag GTPases with unbiased and candidate-based approaches. 2) To establish the consequences of deregulated nutrient-dependent activation of mTORC1 in physiology, by means of genetically engineered mice. 3) To determine the impact of the nutrient sensing pathway in the effects of dietary restriction and nutrient limitation in glucose homeostasis and cancer.
Summary
A major role of metabolic alterations in the development of several human diseases, as diabetes, cancer and in the onset of ageing is becoming increasingly evident. This has a deep impact for human health due to the alarming increase in nutrient intake and obesity in the last decades. Fundamental aspects of how aberrant nutrient fluctuations trigger deregulated hormone levels and endocrine signals have been elucidated, being a prime example the phenomenon of insulin resistance. In contrast, how changes in nutrient levels elicit direct cell-autonomous signal transduction cascades and the consequences of these responses in physiology are less clear.
The signalling circuitry of direct nutrient sensing converges with that of hormones in the regulation of the mechanistic target of rapamycin (mTOR) kinase, a driver of anabolism, cell growth and proliferation. Deregulation of mTORC1 activity underlies the pathogenesis of cancer and diabetes, and its inhibitor rapamycin is approved as an anti-cancer agent and delays ageing from yeast to mammals. In spite of its importance for human disease, our understanding of the nutrient sensing signalling pathway and its impact in physiology is largely incomplete, as only a few years ago the direct molecular link between nutrients and mTORC1 activation, the Rag GTPases, were identified.
The present proposal aims to determine how the nutrient sensing signalling pathway affects mammalian physiology and metabolism, and whether its deregulation contributes to cancer, insulin resistance and aging. In particular, the objectives are: 1) To identify novel regulators of the Rag GTPases with unbiased and candidate-based approaches. 2) To establish the consequences of deregulated nutrient-dependent activation of mTORC1 in physiology, by means of genetically engineered mice. 3) To determine the impact of the nutrient sensing pathway in the effects of dietary restriction and nutrient limitation in glucose homeostasis and cancer.
Max ERC Funding
1 846 494 €
Duration
Start date: 2016-01-01, End date: 2020-12-31
Project acronym OBECAN
Project Role of obesity in the development of hepatocellular carcinoma
Researcher (PI) Guadalupe Sabio Buzo
Host Institution (HI) CENTRO NACIONAL DE INVESTIGACIONESCARDIOVASCULARES CARLOS III (F.S.P.)
Call Details Starting Grant (StG), LS4, ERC-2010-StG_20091118
Summary Obesity is associated with increased risk for epithelial tumors such as hepatocellular carcinoma (HCC). It is not known, however, whether obesity increases the risk for HCC simply because it promotes cirrhosis, a general risk factor for HCC, or through other mechanisms that operate independently of cirrhosis. Among these, obesity is associated with a chronic inflammatory state, with the release of cytokines such as IL-6 and TNFalpha, well-known HCC mediators. Obesity is normally linked to diabetes and in consequence, to hyperinsulinemia. This increase in circulating insulin levels is suggested to be a factor that contributes to cancer. Moreover, the increase in free fatty acids (FFA) in blood among obese patients promotes a compensatory response from liver that activates the transcription of genes required for beta-oxidation, leading to a reduction in non-physiological stores of lipids in the liver. This increase in beta-oxidation could result in oxidative stress, inflammation and the production of lipid peroxidation bioproducts, which are known mutagens. The precise mechanisms whereby FFA and cytosolic triglycerides exert their effects, resulting in the diabetic phenotype, remain poorly understood. Emerging evidence nonetheless links microRNA (miRNA) with lipid metabolism, suggesting that these small RNAs mediate this increase in beta-oxidation.
Our goal is to study how the components of the obesity state (inflammation, steatosis hyperinsulinemia and microRNA control of gene regulation) affect HCC development. We will use several mouse models in which one or more of these factors are reduced following induction of metabolic disease. We will also determine whether specific miRNAs that are down- or upregulated in the liver of mice on a high fat diet are implicated in HCC development.
Summary
Obesity is associated with increased risk for epithelial tumors such as hepatocellular carcinoma (HCC). It is not known, however, whether obesity increases the risk for HCC simply because it promotes cirrhosis, a general risk factor for HCC, or through other mechanisms that operate independently of cirrhosis. Among these, obesity is associated with a chronic inflammatory state, with the release of cytokines such as IL-6 and TNFalpha, well-known HCC mediators. Obesity is normally linked to diabetes and in consequence, to hyperinsulinemia. This increase in circulating insulin levels is suggested to be a factor that contributes to cancer. Moreover, the increase in free fatty acids (FFA) in blood among obese patients promotes a compensatory response from liver that activates the transcription of genes required for beta-oxidation, leading to a reduction in non-physiological stores of lipids in the liver. This increase in beta-oxidation could result in oxidative stress, inflammation and the production of lipid peroxidation bioproducts, which are known mutagens. The precise mechanisms whereby FFA and cytosolic triglycerides exert their effects, resulting in the diabetic phenotype, remain poorly understood. Emerging evidence nonetheless links microRNA (miRNA) with lipid metabolism, suggesting that these small RNAs mediate this increase in beta-oxidation.
Our goal is to study how the components of the obesity state (inflammation, steatosis hyperinsulinemia and microRNA control of gene regulation) affect HCC development. We will use several mouse models in which one or more of these factors are reduced following induction of metabolic disease. We will also determine whether specific miRNAs that are down- or upregulated in the liver of mice on a high fat diet are implicated in HCC development.
Max ERC Funding
1 498 043 €
Duration
Start date: 2010-12-01, End date: 2016-11-30
Project acronym OBERSTRESS
Project Hypothalamic Lipotoxicity and Endoplasmic Reticulum Stress: a New Pathophysiological Mechanism of Obesity
Researcher (PI) Miguel Antonio López Pérez
Host Institution (HI) UNIVERSIDAD DE SANTIAGO DE COMPOSTELA
Call Details Starting Grant (StG), LS4, ERC-2011-StG_20101109
Summary It is well established that metabolically relevant organs such as adipose tissue, pancreatic beta cells, liver and skeletal muscle develop endoplasmic reticulum (ER) stress under conditions of obesity induced lipotoxicity. Here, the applicant will investigate if/how the hypothalamus is affected by lipotoxicity and ER stress in the context of obesity
* Scientific Hypotheses:
1. Obesity is associated with lipotoxicity and ER stress in the hypothalamus.
2. Hypothalamic ER stress may contribute to the development of obesity through dysregulation of the mechanisms controlling energy balance.
3. Based on our preliminary data, we hypothesize that CHOP, a mediator of ER stress, could be a key modulator of the association between obesity and ER dysfunction in the hypothalamus.
* General Objective: to determine the relevance of hypothalamic lipotoxicity and ER stress for the development of obesity and whether targeting ER stress mechanisms is a successful therapeutic strategy to prevent or revert obesity and its metabolic complications.
* Specific Objectives:
1. To determine whether obesity and the metabolic syndrome are associated with hypothalamic lipotoxicity, ER stress and whether these effects are hypothalamic nuclei specific
2. To determine whether primary hypothalamic ER stress is a cause of altered energy balance leading to obesity and metabolic complications
3. To determine whether in the context of obesity inhibition of ER stress in hypothalamus affects energy balance and obesity associated metabolic complications
4. To determine the role of CHOP on energy balance and obesity in specific hypothalamic neuronal populations
This project is central to the applicant’s goal of understanding how the hypothalamus regulates energy balance under physiological and pathophysiological conditions, as an essential step towards identifying and developing novel molecular drug targets to tackle the problem of obesity and their metabolic complications.
Summary
It is well established that metabolically relevant organs such as adipose tissue, pancreatic beta cells, liver and skeletal muscle develop endoplasmic reticulum (ER) stress under conditions of obesity induced lipotoxicity. Here, the applicant will investigate if/how the hypothalamus is affected by lipotoxicity and ER stress in the context of obesity
* Scientific Hypotheses:
1. Obesity is associated with lipotoxicity and ER stress in the hypothalamus.
2. Hypothalamic ER stress may contribute to the development of obesity through dysregulation of the mechanisms controlling energy balance.
3. Based on our preliminary data, we hypothesize that CHOP, a mediator of ER stress, could be a key modulator of the association between obesity and ER dysfunction in the hypothalamus.
* General Objective: to determine the relevance of hypothalamic lipotoxicity and ER stress for the development of obesity and whether targeting ER stress mechanisms is a successful therapeutic strategy to prevent or revert obesity and its metabolic complications.
* Specific Objectives:
1. To determine whether obesity and the metabolic syndrome are associated with hypothalamic lipotoxicity, ER stress and whether these effects are hypothalamic nuclei specific
2. To determine whether primary hypothalamic ER stress is a cause of altered energy balance leading to obesity and metabolic complications
3. To determine whether in the context of obesity inhibition of ER stress in hypothalamus affects energy balance and obesity associated metabolic complications
4. To determine the role of CHOP on energy balance and obesity in specific hypothalamic neuronal populations
This project is central to the applicant’s goal of understanding how the hypothalamus regulates energy balance under physiological and pathophysiological conditions, as an essential step towards identifying and developing novel molecular drug targets to tackle the problem of obesity and their metabolic complications.
Max ERC Funding
1 484 000 €
Duration
Start date: 2011-12-01, End date: 2017-05-31
Project acronym OBESITY53
Project p53 as a New Mediator of Energy Balance in the Brain
Researcher (PI) Ruben Nogueiras Pozo
Host Institution (HI) UNIVERSIDAD DE SANTIAGO DE COMPOSTELA
Call Details Starting Grant (StG), LS4, ERC-2011-StG_20101109
Summary p53 is a transcriptional factor modulating numerous biological actions. Although it is best known for its role in cancer development, it is now evident that it is implicated in metabolism. More specifically, p53 modulates energy metabolism and homeostasis through their effects on adipocyte development and function. However, nothing is known about the potential metabolic function of p53 in the central nervous system.
Neuronal networks within the central nervous system play a crucial role in the regulation of food intake, body weight, and glucose homeostasis, so the main objective of this project will be to evaluate the potential of brain p53 as anti-obesity and/or anti-diabetic drug candidate. Our project will dissect precisely which specific components of energy balance are altered after central disruption or rescue of p53 signalling in selective neuronal populations, as well as the molecular pathways mediating these actions.
More precisely, we will disrupt the central p53 signalling specifically in hypothalamic POMC and AgRP neurons, which are crucial for energy and glucose homeostasis. We will also generate and characterize mice lacking p53 in dopamine neurons that are essential for mechanisms related with the reward of food. Once we know which specific areas are crucial for the central actions of p53, we will complete the experiments rescuing p53 expression in selective neuronal populations (POMC, AgRP or dopamine neurons) of p53 null mice. We will also investigate the interaction between p53 with leptin and ghrelin, likely the two more important hormones in the regulation of energy balance, which act through homeostatic and hedonic mechanisms. Understanding the precise role and mechanisms regulated by central p53 on energy balance may open new avenues for the identification of potential anti-obesity drug targets directed towards specific molecular pathways.
Summary
p53 is a transcriptional factor modulating numerous biological actions. Although it is best known for its role in cancer development, it is now evident that it is implicated in metabolism. More specifically, p53 modulates energy metabolism and homeostasis through their effects on adipocyte development and function. However, nothing is known about the potential metabolic function of p53 in the central nervous system.
Neuronal networks within the central nervous system play a crucial role in the regulation of food intake, body weight, and glucose homeostasis, so the main objective of this project will be to evaluate the potential of brain p53 as anti-obesity and/or anti-diabetic drug candidate. Our project will dissect precisely which specific components of energy balance are altered after central disruption or rescue of p53 signalling in selective neuronal populations, as well as the molecular pathways mediating these actions.
More precisely, we will disrupt the central p53 signalling specifically in hypothalamic POMC and AgRP neurons, which are crucial for energy and glucose homeostasis. We will also generate and characterize mice lacking p53 in dopamine neurons that are essential for mechanisms related with the reward of food. Once we know which specific areas are crucial for the central actions of p53, we will complete the experiments rescuing p53 expression in selective neuronal populations (POMC, AgRP or dopamine neurons) of p53 null mice. We will also investigate the interaction between p53 with leptin and ghrelin, likely the two more important hormones in the regulation of energy balance, which act through homeostatic and hedonic mechanisms. Understanding the precise role and mechanisms regulated by central p53 on energy balance may open new avenues for the identification of potential anti-obesity drug targets directed towards specific molecular pathways.
Max ERC Funding
1 477 680 €
Duration
Start date: 2011-12-01, End date: 2017-05-31
Project acronym OPTICALBULLET
Project Studies of neurosecretion by remote control of exocytosis and endocytosis with ligt
Researcher (PI) Pau Gorostiza
Host Institution (HI) FUNDACIO INSTITUT DE BIOENGINYERIA DE CATALUNYA
Call Details Starting Grant (StG), LS7, ERC-2007-StG
Summary Optical switches are photoisomerizable compounds that allow to remotely controlling the activity of proteins, cells and entire organisms with light. These tools are revolutionizing research in biology with their high selectivity and spatiotemporal resolution. Here we propose to develop and apply optical switches to investigate the fundamental processes of secretion, exocytosis and endocytosis, in a way that is non-invasive, acute, and orthogonal to pharmacological and electrophysiological techniques. The optical control of exocytosis will be carried out by means of photoswitchable, Ca2+-permeable channels (LiGluR and Channelrhodopsin-2) which allow triggering vesicle fusion at single synaptic terminals. This procedure will allow studying vesicle release kinetics and the differences between synapses of the same neuron. The photocontrol of endocytosis will be carried out with: (1) inhibitory peptides of the clathrin pathway modified with an azobenzene crosslinker in order to photomodulate their structure and affinity, and (2) photoswitchable synthetic compounds based on chemical inhibitors of dynamin. Photomodulation of endocytosis in chromaffin cells and neurons will allow interfering with the internalisation of membrane receptors with an unprecedented spatial and temporal control. The use of photoswitchable inhibitors of endocytosis would allow for the first time to manipulate reversibly and with subcellular resolution, the vesicular trafficking of the endocytic pathway. In addition, these photoswitches could reveal how endocytosis regulates spatially receptor activation, controlling cell patterning and cell fate.
Summary
Optical switches are photoisomerizable compounds that allow to remotely controlling the activity of proteins, cells and entire organisms with light. These tools are revolutionizing research in biology with their high selectivity and spatiotemporal resolution. Here we propose to develop and apply optical switches to investigate the fundamental processes of secretion, exocytosis and endocytosis, in a way that is non-invasive, acute, and orthogonal to pharmacological and electrophysiological techniques. The optical control of exocytosis will be carried out by means of photoswitchable, Ca2+-permeable channels (LiGluR and Channelrhodopsin-2) which allow triggering vesicle fusion at single synaptic terminals. This procedure will allow studying vesicle release kinetics and the differences between synapses of the same neuron. The photocontrol of endocytosis will be carried out with: (1) inhibitory peptides of the clathrin pathway modified with an azobenzene crosslinker in order to photomodulate their structure and affinity, and (2) photoswitchable synthetic compounds based on chemical inhibitors of dynamin. Photomodulation of endocytosis in chromaffin cells and neurons will allow interfering with the internalisation of membrane receptors with an unprecedented spatial and temporal control. The use of photoswitchable inhibitors of endocytosis would allow for the first time to manipulate reversibly and with subcellular resolution, the vesicular trafficking of the endocytic pathway. In addition, these photoswitches could reveal how endocytosis regulates spatially receptor activation, controlling cell patterning and cell fate.
Max ERC Funding
1 338 000 €
Duration
Start date: 2008-09-01, End date: 2013-08-31
Project acronym OscillInterference
Project Therapeutic Mechanisms and Long Term Effects of Directed Transcranial Alternating Current Stimulation in Epileptic Seizures
Researcher (PI) Antal Berényi
Host Institution (HI) Szegedi Tudomanyegyetem - Hungarian-Netherlands School of Educational Management
Call Details Starting Grant (StG), LS5, ERC-2013-StG
Summary A significant proportion of patients with epilepsy are refractive to pharmaceutical treatments. Recurrent, untreated epileptic seizures are associated with risk of adverse neurological, cognitive, and psychological outcomes. Despite years of study, there are still significant barriers to the management of these disorders. In my proposal I advance the hypothesis that time-targeted perturbation of neural network oscillations by transcranial electric stimulation (TES) decreases the duration of seizures. I hypothesize further that spatially focused TES and chronically applied TES intervention can also permanently reduce seizure occurrence. Our specific aims are designed to perform in vivo studies in rodent models of two seizure types (absence seizures and complex partial seizures) to evaluate the effectiveness of TES in abrogating pathologic network activity, and to use high resolution recording techniques and optogenetical methods to assess the neural mechanisms involved. Our results may help to establish general principles of the diverse epilepsy pathophysiology and introduce novel therapeutic approaches. We will establish a focal TES stimulation protocol to selectively interfere with brain regions previously identified as key structures in the pathomechanism of epilepsy. The deliverables of these experiments will make a significant advancement in the understanding of the pathomechanisms of these disorders, and will offer a new alternative treatment option as a complimentary therapeutic approach to the state of the art pharmaceutical products. The methods used in this project are unique and advanced as the first attempt to perform 512 channel extracellular recordings in the behaving animal to investigate the evolution of epileptic seizures at the neuronal network and cellular levels and by achieving spatially selective TES. The combination of these methods are deployed for both understanding the mechanisms of seizure evolution, and termination of seizures.
Summary
A significant proportion of patients with epilepsy are refractive to pharmaceutical treatments. Recurrent, untreated epileptic seizures are associated with risk of adverse neurological, cognitive, and psychological outcomes. Despite years of study, there are still significant barriers to the management of these disorders. In my proposal I advance the hypothesis that time-targeted perturbation of neural network oscillations by transcranial electric stimulation (TES) decreases the duration of seizures. I hypothesize further that spatially focused TES and chronically applied TES intervention can also permanently reduce seizure occurrence. Our specific aims are designed to perform in vivo studies in rodent models of two seizure types (absence seizures and complex partial seizures) to evaluate the effectiveness of TES in abrogating pathologic network activity, and to use high resolution recording techniques and optogenetical methods to assess the neural mechanisms involved. Our results may help to establish general principles of the diverse epilepsy pathophysiology and introduce novel therapeutic approaches. We will establish a focal TES stimulation protocol to selectively interfere with brain regions previously identified as key structures in the pathomechanism of epilepsy. The deliverables of these experiments will make a significant advancement in the understanding of the pathomechanisms of these disorders, and will offer a new alternative treatment option as a complimentary therapeutic approach to the state of the art pharmaceutical products. The methods used in this project are unique and advanced as the first attempt to perform 512 channel extracellular recordings in the behaving animal to investigate the evolution of epileptic seizures at the neuronal network and cellular levels and by achieving spatially selective TES. The combination of these methods are deployed for both understanding the mechanisms of seizure evolution, and termination of seizures.
Max ERC Funding
1 419 000 €
Duration
Start date: 2013-11-01, End date: 2018-10-31
Project acronym PD-HUMMODEL
Project Elucidating early pathogenic mechanisms of neurodegeneration in Parkinson's disease through a humanized dynamic in vitro model
Researcher (PI) Antonella Consiglio
Host Institution (HI) UNIVERSITAT DE BARCELONA
Call Details Starting Grant (StG), LS7, ERC-2012-StG_20111109
Summary Our understanding of Parkinson’s disease (PD) pathogenesis is currently limited by difficulties in obtaining live neurons from patients and the inability to model the sporadic, most frequent, form of PD. It may be possible to overcome these challenges by reprogramming somatic cells from patients into induced pluripotent stem cells (iPSC). In preliminary studies, we have generated a collection of 50 iPSC lines representing both sporadic PD and familial PD patients, and identified distinct PD-related neurodegeneration phenotypes arising, upon long-term culture, in DAn differentiated from these PD-iPSC. Here, I propose to take advantage of this genuinely human PD model to investigate: i) mechanistic insights responsible for the PD phenotype identified in our model (by combining molecular and biochemical analyses to study mitochondrial function and redox profile, as well as genome-wide transcriptional profile of control versus PD-patient specific iPSC-derived DAn); ii) early functional alterations in patient-specific iPSC-derived DAn, which would predate neurodegeneration signs and provide valuable information as to ways to prevent, rather than rescue, neurodegeneration in PD patients (by electrophysiological recordings in in vitro reconstructed neuronal/glial networks to assess synaptic dynamics together with neuronal excitability); iii) further refinements in our iPSC-based PD model, including the generation of iPSC lines representing asymptomatic patients carrying pathogenic mutations, and the correction of known mutations by gene edition, all of which will allow exploring the relationship between pathogenic mutations and the genetic makeup of patients; and iv) whether DAn degeneration in PD is solely a cell-autonomous phenomenon, or whether it is influenced by an altered cross-talk between DAn and glial cells. These studies may impact significantly on our understanding of PD pathogenesis and on the development of new therapy strategy.
Summary
Our understanding of Parkinson’s disease (PD) pathogenesis is currently limited by difficulties in obtaining live neurons from patients and the inability to model the sporadic, most frequent, form of PD. It may be possible to overcome these challenges by reprogramming somatic cells from patients into induced pluripotent stem cells (iPSC). In preliminary studies, we have generated a collection of 50 iPSC lines representing both sporadic PD and familial PD patients, and identified distinct PD-related neurodegeneration phenotypes arising, upon long-term culture, in DAn differentiated from these PD-iPSC. Here, I propose to take advantage of this genuinely human PD model to investigate: i) mechanistic insights responsible for the PD phenotype identified in our model (by combining molecular and biochemical analyses to study mitochondrial function and redox profile, as well as genome-wide transcriptional profile of control versus PD-patient specific iPSC-derived DAn); ii) early functional alterations in patient-specific iPSC-derived DAn, which would predate neurodegeneration signs and provide valuable information as to ways to prevent, rather than rescue, neurodegeneration in PD patients (by electrophysiological recordings in in vitro reconstructed neuronal/glial networks to assess synaptic dynamics together with neuronal excitability); iii) further refinements in our iPSC-based PD model, including the generation of iPSC lines representing asymptomatic patients carrying pathogenic mutations, and the correction of known mutations by gene edition, all of which will allow exploring the relationship between pathogenic mutations and the genetic makeup of patients; and iv) whether DAn degeneration in PD is solely a cell-autonomous phenomenon, or whether it is influenced by an altered cross-talk between DAn and glial cells. These studies may impact significantly on our understanding of PD pathogenesis and on the development of new therapy strategy.
Max ERC Funding
1 324 802 €
Duration
Start date: 2013-07-01, End date: 2018-06-30
Project acronym PHYGENOM
Project Models of genome evolution, phylogenomics and the tree of life
Researcher (PI) David Posada
Host Institution (HI) UNIVERSIDAD DE VIGO
Call Details Starting Grant (StG), LS2, ERC-2007-StG
Summary Understanding the evolution of all living organisms is one of the fundamental challenges in biology. The phylogenetic analysis of whole genomes has already proven very useful to decipher not only their history, but also their organization and function. Indeed, the accuracy of these inferences is intimately related to the quality of the models assumed. Despite important advances, models of genome evolution are still in its infancy, and more realistic models are needed to provide more precise and reliable inferences from genome data. In addition, a number of phylogenomic algorithms have been proposed to estimate phylogenies from complete genomes based on different genomic features. Although the application of these methods has already led to critical conclusions regarding the tree of life, the relative performance of these algorithms has not been properly evaluated yet. The first objective of this grant is to develop more realistic models of genome evolution, integrating changes in gene content and changes in gene sequences, and allowing for model variation along different branches of the phylogeny. In order to avoid model overparameterization, a statistical framework for the selection of best-fit models of genome evolution for the data at hand will also be implemented. Genome data simulated under these models will be used to compare the performance of different phylogenomic algorithms. Optimized phylogenomic strategies will then be applied to available genomes in order to decipher unresolved portions of the tree of life. Finally, all the bioinformatic tools developed under this grant will be made freely available to the scientific community.
Summary
Understanding the evolution of all living organisms is one of the fundamental challenges in biology. The phylogenetic analysis of whole genomes has already proven very useful to decipher not only their history, but also their organization and function. Indeed, the accuracy of these inferences is intimately related to the quality of the models assumed. Despite important advances, models of genome evolution are still in its infancy, and more realistic models are needed to provide more precise and reliable inferences from genome data. In addition, a number of phylogenomic algorithms have been proposed to estimate phylogenies from complete genomes based on different genomic features. Although the application of these methods has already led to critical conclusions regarding the tree of life, the relative performance of these algorithms has not been properly evaluated yet. The first objective of this grant is to develop more realistic models of genome evolution, integrating changes in gene content and changes in gene sequences, and allowing for model variation along different branches of the phylogeny. In order to avoid model overparameterization, a statistical framework for the selection of best-fit models of genome evolution for the data at hand will also be implemented. Genome data simulated under these models will be used to compare the performance of different phylogenomic algorithms. Optimized phylogenomic strategies will then be applied to available genomes in order to decipher unresolved portions of the tree of life. Finally, all the bioinformatic tools developed under this grant will be made freely available to the scientific community.
Max ERC Funding
994 800 €
Duration
Start date: 2008-10-01, End date: 2013-09-30
