Project acronym CICHLIDX
Project An integrative approach towards the understanding of an adaptive radiation of East African cichlid fishes
Researcher (PI) Walter Salzburger
Host Institution (HI) UNIVERSITAT BASEL
Country Switzerland
Call Details Consolidator Grant (CoG), LS8, ERC-2013-CoG
Summary "More than 150 years after the publication of Charles Darwin’s The Origin of Species, the identification of the processes that govern the emergence of novel species remains a fundamental problem to biology. Why is it that some groups have diversified in a seemingly explosive manner, while others have lingered unvaried over millions of years? What are the external factors and environmental conditions that promote organismal diversity? And what is the molecular basis of adaptation and diversification? A key to these and related questions is the comparative study of exceptionally diverse yet relatively recent species assemblages such as Darwin’s finches, the Caribbean anole lizards, or the hundreds of endemic species of cichlid fishes in the East African Great Lakes, which are at the center of this proposal. More specifically, I intend to conduct the so far most thorough examination of a large adaptive radiation, combining in-depth eco-morphological assessments and whole genome sequencing of all members of a cichlid species flock. To this end, I plan to (i) sequence the genomes and transcriptomes of several specimens of each cichlid species from Lake Tanganyika to examine genetic and transcriptional diversity; (ii) apply stable-isotope and stomach-content analyses in combination with underwater transplant experiments and transect surveys to quantitate feeding performances, habitat preferences and natural-history parameters; (iii) use X-ray computed tomography to study phenotypic variation in 3D; and (iv) examine fossils from existing and forthcoming drilling cores to implement a time line of diversification in a cichlid adaptive radiation. This project, thus, offers the unique opportunity to test recent theory- and data-based predictions on speciation and adaptive radiation within an entire biological system – in this case the adaptive radiation of cichlid fishes in Lake Tanganyika."
Summary
"More than 150 years after the publication of Charles Darwin’s The Origin of Species, the identification of the processes that govern the emergence of novel species remains a fundamental problem to biology. Why is it that some groups have diversified in a seemingly explosive manner, while others have lingered unvaried over millions of years? What are the external factors and environmental conditions that promote organismal diversity? And what is the molecular basis of adaptation and diversification? A key to these and related questions is the comparative study of exceptionally diverse yet relatively recent species assemblages such as Darwin’s finches, the Caribbean anole lizards, or the hundreds of endemic species of cichlid fishes in the East African Great Lakes, which are at the center of this proposal. More specifically, I intend to conduct the so far most thorough examination of a large adaptive radiation, combining in-depth eco-morphological assessments and whole genome sequencing of all members of a cichlid species flock. To this end, I plan to (i) sequence the genomes and transcriptomes of several specimens of each cichlid species from Lake Tanganyika to examine genetic and transcriptional diversity; (ii) apply stable-isotope and stomach-content analyses in combination with underwater transplant experiments and transect surveys to quantitate feeding performances, habitat preferences and natural-history parameters; (iii) use X-ray computed tomography to study phenotypic variation in 3D; and (iv) examine fossils from existing and forthcoming drilling cores to implement a time line of diversification in a cichlid adaptive radiation. This project, thus, offers the unique opportunity to test recent theory- and data-based predictions on speciation and adaptive radiation within an entire biological system – in this case the adaptive radiation of cichlid fishes in Lake Tanganyika."
Max ERC Funding
1 999 238 €
Duration
Start date: 2014-03-01, End date: 2019-02-28
Project acronym MUSCLE-NET
Project Coactivator-controlled transcriptional networks regulating skeletal muscle cell plasticity
Researcher (PI) Christoph Handschin
Host Institution (HI) UNIVERSITAT BASEL
Country Switzerland
Call Details Consolidator Grant (CoG), LS4, ERC-2013-CoG
Summary "Regular physical activity is linked to improved health and increased life expectancy. Inversely, a sedentary life-style is a strong and independent risk factor for many chronic diseases, including obesity, type 2 diabetes or cardiovascular disorders, as well as certain types of cancer or neurodegeneration. Interestingly however, the molecular mechanisms that mediate the health beneficial effects of exercise, or those that trigger the pathological changes in diseases, are largely unknown.
The transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is one of the major regulatory hubs of muscle adaptation to endurance training. Accordingly, elevated expression of PGC-1α in muscle is sufficient to induce a trained phenotype in mice. Inversely, mice lacking a functional PGC-1α gene in skeletal muscle exhibit many signs of pathological inactivity. Finally, PGC-1α expression is dysregulated in pathological contexts in human muscle, including type 2 diabetes and aging. Therefore, the study of the regulation and function of PGC-1α in muscle has the potential to yield important insights into the molecular mechanisms that control muscle health.
Unfortunately, the characterization of PGC-1α is drastically hampered by the high complexity of the transcriptional network controlled by this coactivator protein, which binds to many different transcription factor binding partners in a cell context-specific manner. Moreover, PGC-1α seems to directly couple transcription to RNA processing, thereby further complicating the analysis of PGC-1α-controlled biological programs. Our proposal combines novel innovative experimental and biocomputational approaches with the physiological study of healthy and diseased muscle cells ex vivo and in different animal models targeted on PGC-1α. Together, our findings will reveal novel insights on muscle function and may substantially shape the development of exercise mimetic-based therapies."
Summary
"Regular physical activity is linked to improved health and increased life expectancy. Inversely, a sedentary life-style is a strong and independent risk factor for many chronic diseases, including obesity, type 2 diabetes or cardiovascular disorders, as well as certain types of cancer or neurodegeneration. Interestingly however, the molecular mechanisms that mediate the health beneficial effects of exercise, or those that trigger the pathological changes in diseases, are largely unknown.
The transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is one of the major regulatory hubs of muscle adaptation to endurance training. Accordingly, elevated expression of PGC-1α in muscle is sufficient to induce a trained phenotype in mice. Inversely, mice lacking a functional PGC-1α gene in skeletal muscle exhibit many signs of pathological inactivity. Finally, PGC-1α expression is dysregulated in pathological contexts in human muscle, including type 2 diabetes and aging. Therefore, the study of the regulation and function of PGC-1α in muscle has the potential to yield important insights into the molecular mechanisms that control muscle health.
Unfortunately, the characterization of PGC-1α is drastically hampered by the high complexity of the transcriptional network controlled by this coactivator protein, which binds to many different transcription factor binding partners in a cell context-specific manner. Moreover, PGC-1α seems to directly couple transcription to RNA processing, thereby further complicating the analysis of PGC-1α-controlled biological programs. Our proposal combines novel innovative experimental and biocomputational approaches with the physiological study of healthy and diseased muscle cells ex vivo and in different animal models targeted on PGC-1α. Together, our findings will reveal novel insights on muscle function and may substantially shape the development of exercise mimetic-based therapies."
Max ERC Funding
1 999 397 €
Duration
Start date: 2014-04-01, End date: 2019-03-31
Project acronym NeuroVision
Project The organisation of functional microcircuits in visual cortex
Researcher (PI) Thomas Mrsic-Flogel
Host Institution (HI) UNIVERSITAT BASEL
Country Switzerland
Call Details Consolidator Grant (CoG), LS5, ERC-2013-CoG
Summary Determining how the organisation of neural circuitry gives rise to its function has been a major challenge for understanding the neural basis of perception and behaviour. In order to uncover how different regions of the neocortex process sensory information, it is necessary to understand how the pattern and properties of synaptic connections in a specific sensory circuit determine the computations it performs. I propose to establish the relationship between synaptic connectivity and neuronal function in primary visual cortex (V1) with the aim of revealing circuit-level mechanisms of sensory processing. To this end, my laboratory has developed a new method, by which visual response properties of neurons are first characterised with two-photon calcium imaging in vivo, and then synaptic connections between a subset of these neurons are assayed with multiple whole-cell recordings in slices of the same tissue. We will use this method to determine how connectivity, synaptic and intrinsic properties of different excitatory and inhibitory cell types relate to the emergence of their visual receptive fields (RFs). Specifically, we will test the dependence of connections on RF position, structure and other visual response properties, the specificity of connections between simple and complex cells, and the relative contribution of feedforward and recurrent excitation and inhibition towards shaping RFs. Morphological, physiological, connectional and functional data will be used to develop a biophysically realistic network model of this V1 circuit to examine the contribution of different circuit components to single-neuron and network function.
Summary
Determining how the organisation of neural circuitry gives rise to its function has been a major challenge for understanding the neural basis of perception and behaviour. In order to uncover how different regions of the neocortex process sensory information, it is necessary to understand how the pattern and properties of synaptic connections in a specific sensory circuit determine the computations it performs. I propose to establish the relationship between synaptic connectivity and neuronal function in primary visual cortex (V1) with the aim of revealing circuit-level mechanisms of sensory processing. To this end, my laboratory has developed a new method, by which visual response properties of neurons are first characterised with two-photon calcium imaging in vivo, and then synaptic connections between a subset of these neurons are assayed with multiple whole-cell recordings in slices of the same tissue. We will use this method to determine how connectivity, synaptic and intrinsic properties of different excitatory and inhibitory cell types relate to the emergence of their visual receptive fields (RFs). Specifically, we will test the dependence of connections on RF position, structure and other visual response properties, the specificity of connections between simple and complex cells, and the relative contribution of feedforward and recurrent excitation and inhibition towards shaping RFs. Morphological, physiological, connectional and functional data will be used to develop a biophysically realistic network model of this V1 circuit to examine the contribution of different circuit components to single-neuron and network function.
Max ERC Funding
1 983 289 €
Duration
Start date: 2014-05-01, End date: 2019-04-30
Project acronym ReStreCa
Project DNA Replication Stress in Cancer
Researcher (PI) Massimo Lopes
Host Institution (HI) University of Zurich
Country Switzerland
Call Details Consolidator Grant (CoG), LS1, ERC-2013-CoG
Summary DNA replication is a crucial, but potentially dangerous process in every cellular division. A failure to maintain the integrity of replicating chromosomes leads to genome instability, an early event in tumorigenesis. Most common anti-cancer drugs also interfere with DNA synthesis, by largely undefined mechanisms. My lab specializes in the structural and molecular characterization of DNA replication stress in higher eukaryotes, combining standard cell and molecular biology with specialized single molecule analysis of replication intermediates.
The first aim of our research is to gain mechanistic information about the elusive impact of oncogene activation on DNA replication. By direct structural analysis of tissue culture models of tumorigenesis, we have recently uncovered specific defects in DNA synthesis associated with DNA damage checkpoint activation. We plan to expand these studies to compare the effect of different oncogenes and to identify cellular factors modulating oncogene-induced genotoxicity.
We are also elucidating the cytotoxic mechanisms of anti-cancer drugs that challenge DNA replication. Comparing the molecular consequences of chemotherapeutic treatments in control cells and cells lacking cancer-related factors, we plan to uncover how precisely different drugs interfere with replication and which cellular players mediate their cytotoxicity. We plan to complement these studies with a proteomic-based screen, to identify novel factors modulating replication of a damaged template.
Finally, we plan to analyze replication features in different populations of stem cells, as the cellular response to replication stress was recently proven essential for stem cell maintenance. We aim to provide mechanistic insight into the constitutive activation of the DNA damage response reported in embryonic stem cells. We also plan to expand these investigations to hematopoietic stem cells, where we recently observed similar phenomena upon stimuli-induced proliferation.
Summary
DNA replication is a crucial, but potentially dangerous process in every cellular division. A failure to maintain the integrity of replicating chromosomes leads to genome instability, an early event in tumorigenesis. Most common anti-cancer drugs also interfere with DNA synthesis, by largely undefined mechanisms. My lab specializes in the structural and molecular characterization of DNA replication stress in higher eukaryotes, combining standard cell and molecular biology with specialized single molecule analysis of replication intermediates.
The first aim of our research is to gain mechanistic information about the elusive impact of oncogene activation on DNA replication. By direct structural analysis of tissue culture models of tumorigenesis, we have recently uncovered specific defects in DNA synthesis associated with DNA damage checkpoint activation. We plan to expand these studies to compare the effect of different oncogenes and to identify cellular factors modulating oncogene-induced genotoxicity.
We are also elucidating the cytotoxic mechanisms of anti-cancer drugs that challenge DNA replication. Comparing the molecular consequences of chemotherapeutic treatments in control cells and cells lacking cancer-related factors, we plan to uncover how precisely different drugs interfere with replication and which cellular players mediate their cytotoxicity. We plan to complement these studies with a proteomic-based screen, to identify novel factors modulating replication of a damaged template.
Finally, we plan to analyze replication features in different populations of stem cells, as the cellular response to replication stress was recently proven essential for stem cell maintenance. We aim to provide mechanistic insight into the constitutive activation of the DNA damage response reported in embryonic stem cells. We also plan to expand these investigations to hematopoietic stem cells, where we recently observed similar phenomena upon stimuli-induced proliferation.
Max ERC Funding
1 846 500 €
Duration
Start date: 2014-10-01, End date: 2019-09-30
