Project acronym CONCEPT
Project Construction of Perception from Touch Signals
Researcher (PI) Mathew Diamond
Host Institution (HI) SCUOLA INTERNAZIONALE SUPERIORE DI STUDI AVANZATI DI TRIESTE
Call Details Advanced Grant (AdG), LS5, ERC-2011-ADG_20110310
Summary Our sensory systems gather stimuli as elemental physical features yet we perceive a world made up of familiar objects, not wavelengths or vibrations. Perception occurs when the neuronal representation of physical parameters is transformed into the neuronal representation of meaningful objects. How does this recoding occur? An ideal platform for the inquiry is the rat whisker sensory system: it produces fast and accurate judgments of complex stimuli, yet can be broken down into accessible neuronal mechanisms. CONCEPT will examine the process that begins with whisker motion and ends with perception of the contacted object. Understanding the general principles for the construction of perception will help explain why we experience the world as we do.
The main hypothesis is that graded neuronal representations at early processing stages are “fractured” to generate discrete object representations at late processing stages. Of particular interest is the emergence of object representations as the meaning of new stimuli is acquired.
We will collect multi-site single-unit and local field potential signals simultaneously with precise behavioral indices, and will interpret data through advanced computational methods. We will begin by quantifying whisker motion as rats discriminate texture, thus defining the raw material on which the brain operates. Next, we will characterize the transformation of texture along an intracortical stream from sensory areas (where we expect that neurons encode whisker kinematics) to frontal and rhinal areas (where we expect that neurons encode objects extracted from the graded physical continuum) and hippocampus (where we expect that neurons encode objects in conjunction with context). We will test candidate processing schemes by manipulating perception on single trials using optogenetic methods.
Summary
Our sensory systems gather stimuli as elemental physical features yet we perceive a world made up of familiar objects, not wavelengths or vibrations. Perception occurs when the neuronal representation of physical parameters is transformed into the neuronal representation of meaningful objects. How does this recoding occur? An ideal platform for the inquiry is the rat whisker sensory system: it produces fast and accurate judgments of complex stimuli, yet can be broken down into accessible neuronal mechanisms. CONCEPT will examine the process that begins with whisker motion and ends with perception of the contacted object. Understanding the general principles for the construction of perception will help explain why we experience the world as we do.
The main hypothesis is that graded neuronal representations at early processing stages are “fractured” to generate discrete object representations at late processing stages. Of particular interest is the emergence of object representations as the meaning of new stimuli is acquired.
We will collect multi-site single-unit and local field potential signals simultaneously with precise behavioral indices, and will interpret data through advanced computational methods. We will begin by quantifying whisker motion as rats discriminate texture, thus defining the raw material on which the brain operates. Next, we will characterize the transformation of texture along an intracortical stream from sensory areas (where we expect that neurons encode whisker kinematics) to frontal and rhinal areas (where we expect that neurons encode objects extracted from the graded physical continuum) and hippocampus (where we expect that neurons encode objects in conjunction with context). We will test candidate processing schemes by manipulating perception on single trials using optogenetic methods.
Max ERC Funding
2 500 000 €
Duration
Start date: 2012-06-01, End date: 2018-05-31
Project acronym FAST
Project Investigating new therapeutic approaches to Friedreich's Ataxia
Researcher (PI) Roberto Testi
Host Institution (HI) UNIVERSITA DEGLI STUDI DI ROMA TOR VERGATA
Call Details Advanced Grant (AdG), LS7, ERC-2011-ADG_20110310
Summary Friedreich’s Ataxia (FRDA) is a devastating degenerative disease with no specific therapy. It is passed by autosomal recessive inheritance and affects 1:30,000 individuals in Caucasian populations. Symptoms appear in the first decade of life and include progressive and unremitting lack of movement coordination, leading to complete inability, and dilated cardiomyopathy leading to congestive heart failure, the most common cause of premature death. FRDA is due to the insufficient transcription of the gene coding for the mitochondrial protein frataxin. Reduced cellular levels of frataxin cause impaired mitochondrial function and increased sensitivity to oxidative stress, leading to accelerated cell death in critical tissues.
Severity of the disease critically depends on residual frataxin levels. Therapeutic efforts are mostly focused on increasing cellular frataxin . We found that frataxin is normally degraded by the ubiquitin-proteasome system. We identified the lysine responsible for the ubiquitination of frataxin and, by computational screening followed by experimental validation, we identified and validated a series of small molecules, called ubiquitin-competing molecules (UCM), that prevent frataxin ubiquitination and induce frataxin accumulation in cells derived from FRDA patients. Moreover, treatment with UCM partially rescues aconitase and ATP production defects in cells derived from FRDA patients.
Our goal is two fold: 1) submit a set of leads we already identified, as well as their new and more complex derivatives, to preclinical testing in FRDA mice 2) identify the E3 ligase that is responsible for frataxin ubiquitination, and investigate the possibility to use it as a druggable target for small molecules to prevent frataxin degradation.
Summary
Friedreich’s Ataxia (FRDA) is a devastating degenerative disease with no specific therapy. It is passed by autosomal recessive inheritance and affects 1:30,000 individuals in Caucasian populations. Symptoms appear in the first decade of life and include progressive and unremitting lack of movement coordination, leading to complete inability, and dilated cardiomyopathy leading to congestive heart failure, the most common cause of premature death. FRDA is due to the insufficient transcription of the gene coding for the mitochondrial protein frataxin. Reduced cellular levels of frataxin cause impaired mitochondrial function and increased sensitivity to oxidative stress, leading to accelerated cell death in critical tissues.
Severity of the disease critically depends on residual frataxin levels. Therapeutic efforts are mostly focused on increasing cellular frataxin . We found that frataxin is normally degraded by the ubiquitin-proteasome system. We identified the lysine responsible for the ubiquitination of frataxin and, by computational screening followed by experimental validation, we identified and validated a series of small molecules, called ubiquitin-competing molecules (UCM), that prevent frataxin ubiquitination and induce frataxin accumulation in cells derived from FRDA patients. Moreover, treatment with UCM partially rescues aconitase and ATP production defects in cells derived from FRDA patients.
Our goal is two fold: 1) submit a set of leads we already identified, as well as their new and more complex derivatives, to preclinical testing in FRDA mice 2) identify the E3 ligase that is responsible for frataxin ubiquitination, and investigate the possibility to use it as a druggable target for small molecules to prevent frataxin degradation.
Max ERC Funding
1 496 200 €
Duration
Start date: 2012-03-01, End date: 2015-02-28
Project acronym FUNMETA
Project Metabolomics of fungal diseases: a systems biology approach for biomarkers discovery and therapy
Researcher (PI) Luigina Romani
Host Institution (HI) UNIVERSITA DEGLI STUDI DI PERUGIA
Call Details Advanced Grant (AdG), LS7, ERC-2011-ADG_20110310
Summary Humans have evolved intimate symbiotic relationships with a consortium of gut microbes (including fungi) and individual variations in the microbiome influence host health and disease. The fact that fungi are capable of colonizing almost every niche within the human body suggests that they must possess particular immune adaptation mechanisms, the breakdown of which may result in fatal fungal infections and severe fungal diseases. Traditional reductionist approaches of the past have not been sufficient to address these new challenges in the pathogenesis of fungal diseases. Here, I propose an integrated, systems biology approach to understand the role of L-tryptophan (trp) metabolic pathways in multilevel host−fungus interactions. Present in mammals as well as in fungi, pathways of trp metabolic pathways are exploited by the host and the fungal biota for survival and immune adaptation. A variety of indole derivatives, generated through conversion from dietary trp by symbiotic bacteria, activate the aryl hydrocarbon receptor/IL-22 pathway that provides antifungal resistance and tissue repair. Harmful inflammatory responses to fungi are instead tamed by kynurenines generated via the enzyme indoleamine 2,3–dioxygenase (IDO) of the trp pathway. Through high-throughput wet-lab ‘omics’ techniques combined with computational techniques, the project aims at defining the molecular basis of mammalian and fungal IDO activity and a metabolic network linking the metabolic phenotype (metabotype) to immune adaptations and its possible breakdown in experimental and human fungal infections. The project will provide ideal post-graduate training focussed on the development of metabolomics for diagnosis of fungal diseases and optimization of current antifungal therapy and diet that are of relevance to public health care solutions.
Summary
Humans have evolved intimate symbiotic relationships with a consortium of gut microbes (including fungi) and individual variations in the microbiome influence host health and disease. The fact that fungi are capable of colonizing almost every niche within the human body suggests that they must possess particular immune adaptation mechanisms, the breakdown of which may result in fatal fungal infections and severe fungal diseases. Traditional reductionist approaches of the past have not been sufficient to address these new challenges in the pathogenesis of fungal diseases. Here, I propose an integrated, systems biology approach to understand the role of L-tryptophan (trp) metabolic pathways in multilevel host−fungus interactions. Present in mammals as well as in fungi, pathways of trp metabolic pathways are exploited by the host and the fungal biota for survival and immune adaptation. A variety of indole derivatives, generated through conversion from dietary trp by symbiotic bacteria, activate the aryl hydrocarbon receptor/IL-22 pathway that provides antifungal resistance and tissue repair. Harmful inflammatory responses to fungi are instead tamed by kynurenines generated via the enzyme indoleamine 2,3–dioxygenase (IDO) of the trp pathway. Through high-throughput wet-lab ‘omics’ techniques combined with computational techniques, the project aims at defining the molecular basis of mammalian and fungal IDO activity and a metabolic network linking the metabolic phenotype (metabotype) to immune adaptations and its possible breakdown in experimental and human fungal infections. The project will provide ideal post-graduate training focussed on the development of metabolomics for diagnosis of fungal diseases and optimization of current antifungal therapy and diet that are of relevance to public health care solutions.
Max ERC Funding
2 299 200 €
Duration
Start date: 2012-04-01, End date: 2018-03-31
