Project acronym AAMDDR
Project DNA damage response and genome stability: The role of ATM, ATR and the Mre11 complex
Researcher (PI) Vincenzo Costanzo
Host Institution (HI) CANCER RESEARCH UK LBG
Call Details Starting Grant (StG), LS1, ERC-2007-StG
Summary Chromosomal DNA is continuously subjected to exogenous and endogenous damaging insults. In the presence of DNA damage cells activate a multi-faceted checkpoint response that delays cell cycle progression and promotes DNA repair. Failures in this response lead to genomic instability, the main feature of cancer cells. Several cancer-prone human syndromes including the Ataxia teleangiectasia (A-T), the A-T Like Disorder (ATLD) and the Seckel Syndrome reflect defects in the specific genes of the DNA damage response such as ATM, MRE11 and ATR. DNA damage response pathways are poorly understood at biochemical level in vertebrate organisms. We have established a cell-free system based on Xenopus laevis egg extract to study molecular events underlying DNA damage response. This is the first in vitro system that recapitulates different aspects of the DNA damage response in vertebrates. Using this system we propose to study the biochemistry of the ATM, ATR and the Mre11 complex dependent DNA damage response. In particular we will: 1) Dissect the signal transduction pathway that senses DNA damage and promotes cell cycle arrest and DNA damage repair; 2) Analyze at molecular level the role of ATM, ATR, Mre11 in chromosomal DNA replication and mitosis during normal and stressful conditions; 3) Identify substrates of the ATM and ATR dependent DNA damage response using an innovative screening procedure.
Summary
Chromosomal DNA is continuously subjected to exogenous and endogenous damaging insults. In the presence of DNA damage cells activate a multi-faceted checkpoint response that delays cell cycle progression and promotes DNA repair. Failures in this response lead to genomic instability, the main feature of cancer cells. Several cancer-prone human syndromes including the Ataxia teleangiectasia (A-T), the A-T Like Disorder (ATLD) and the Seckel Syndrome reflect defects in the specific genes of the DNA damage response such as ATM, MRE11 and ATR. DNA damage response pathways are poorly understood at biochemical level in vertebrate organisms. We have established a cell-free system based on Xenopus laevis egg extract to study molecular events underlying DNA damage response. This is the first in vitro system that recapitulates different aspects of the DNA damage response in vertebrates. Using this system we propose to study the biochemistry of the ATM, ATR and the Mre11 complex dependent DNA damage response. In particular we will: 1) Dissect the signal transduction pathway that senses DNA damage and promotes cell cycle arrest and DNA damage repair; 2) Analyze at molecular level the role of ATM, ATR, Mre11 in chromosomal DNA replication and mitosis during normal and stressful conditions; 3) Identify substrates of the ATM and ATR dependent DNA damage response using an innovative screening procedure.
Max ERC Funding
1 000 000 €
Duration
Start date: 2008-07-01, End date: 2013-06-30
Project acronym ADIPODIF
Project Adipocyte Differentiation and Metabolic Functions in Obesity and Type 2 Diabetes
Researcher (PI) Christian Wolfrum
Host Institution (HI) EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH
Call Details Starting Grant (StG), LS6, ERC-2007-StG
Summary Obesity associated disorders such as T2D, hypertension and CVD, commonly referred to as the “metabolic syndrome”, are prevalent diseases of industrialized societies. Deranged adipose tissue proliferation and differentiation contribute significantly to the development of these metabolic disorders. Comparatively little however is known, about how these processes influence the development of metabolic disorders. Using a multidisciplinary approach, I plan to elucidate molecular mechanisms underlying the altered adipocyte differentiation and maturation in different models of obesity associated metabolic disorders. Special emphasis will be given to the analysis of gene expression, postranslational modifications and lipid molecular species composition. To achieve this goal, I am establishing several novel methods to isolate pure primary preadipocytes including a new animal model that will allow me to monitor preadipocytes, in vivo and track their cellular fate in the context of a complete organism. These systems will allow, for the first time to study preadipocyte biology, in an in vivo setting. By monitoring preadipocyte differentiation in vivo, I will also be able to answer the key questions regarding the development of preadipocytes and examine signals that induce or inhibit their differentiation. Using transplantation techniques, I will elucidate the genetic and environmental contributions to the progression of obesity and its associated metabolic disorders. Furthermore, these studies will integrate a lipidomics approach to systematically analyze lipid molecular species composition in different models of metabolic disorders. My studies will provide new insights into the mechanisms and dynamics underlying adipocyte differentiation and maturation, and relate them to metabolic disorders. Detailed knowledge of these mechanisms will facilitate development of novel therapeutic approaches for the treatment of obesity and associated metabolic disorders.
Summary
Obesity associated disorders such as T2D, hypertension and CVD, commonly referred to as the “metabolic syndrome”, are prevalent diseases of industrialized societies. Deranged adipose tissue proliferation and differentiation contribute significantly to the development of these metabolic disorders. Comparatively little however is known, about how these processes influence the development of metabolic disorders. Using a multidisciplinary approach, I plan to elucidate molecular mechanisms underlying the altered adipocyte differentiation and maturation in different models of obesity associated metabolic disorders. Special emphasis will be given to the analysis of gene expression, postranslational modifications and lipid molecular species composition. To achieve this goal, I am establishing several novel methods to isolate pure primary preadipocytes including a new animal model that will allow me to monitor preadipocytes, in vivo and track their cellular fate in the context of a complete organism. These systems will allow, for the first time to study preadipocyte biology, in an in vivo setting. By monitoring preadipocyte differentiation in vivo, I will also be able to answer the key questions regarding the development of preadipocytes and examine signals that induce or inhibit their differentiation. Using transplantation techniques, I will elucidate the genetic and environmental contributions to the progression of obesity and its associated metabolic disorders. Furthermore, these studies will integrate a lipidomics approach to systematically analyze lipid molecular species composition in different models of metabolic disorders. My studies will provide new insights into the mechanisms and dynamics underlying adipocyte differentiation and maturation, and relate them to metabolic disorders. Detailed knowledge of these mechanisms will facilitate development of novel therapeutic approaches for the treatment of obesity and associated metabolic disorders.
Max ERC Funding
1 607 105 €
Duration
Start date: 2008-07-01, End date: 2013-06-30
Project acronym AVIANEGG
Project Evolutionary genetics in a ‘classical’ avian study system by high throughput transcriptome sequencing and SNP genotyping
Researcher (PI) Jon Slate
Host Institution (HI) THE UNIVERSITY OF SHEFFIELD
Call Details Starting Grant (StG), LS5, ERC-2007-StG
Summary Long-term studies of free-living vertebrate populations have proved a rich resource for understanding evolutionary and ecological processes, because individuals’ life histories can be measured by tracking them from birth/hatching through to death. In recent years the ‘animal model’ has been applied to pedigreed long-term study populations with great success, dramatically advancing our understanding of quantitative genetic parameters such as heritabilities, genetic correlations and plasticities of traits that are relevant to microevolutionary responses to environmental change. Unfortunately, quantitative genetic approaches have one major drawback – they cannot identify the actual genes responsible for genetic variation. Therefore, it is impossible to link evolutionary responses to a changing environment to molecular genetic variation, making our picture of the process incomplete. Many of the best long-term studies have been conducted in passerine birds. Unfortunately genomics resources are only available for two model avian species, and are absent for bird species that are studied in the wild. I will fill this gap by exploiting recent advances in genomics technology to sequence the entire transcriptome of the longest running study of wild birds – the great tit population in Wytham Woods, Oxford. Having identified most of the sequence variation in the great tit transcriptome, I will then genotype all birds for whom phenotype records and blood samples are available This will be, by far, the largest phenotype-genotype dataset of any free-living vertebrate population. I will then use gene mapping techniques to identify genes and genomic regions responsible for variation in a number of key traits such as lifetime recruitment, clutch size and breeding/laying date. This will result in a greater understanding, at the molecular level, how microevolutionary change can arise (or be constrained).
Summary
Long-term studies of free-living vertebrate populations have proved a rich resource for understanding evolutionary and ecological processes, because individuals’ life histories can be measured by tracking them from birth/hatching through to death. In recent years the ‘animal model’ has been applied to pedigreed long-term study populations with great success, dramatically advancing our understanding of quantitative genetic parameters such as heritabilities, genetic correlations and plasticities of traits that are relevant to microevolutionary responses to environmental change. Unfortunately, quantitative genetic approaches have one major drawback – they cannot identify the actual genes responsible for genetic variation. Therefore, it is impossible to link evolutionary responses to a changing environment to molecular genetic variation, making our picture of the process incomplete. Many of the best long-term studies have been conducted in passerine birds. Unfortunately genomics resources are only available for two model avian species, and are absent for bird species that are studied in the wild. I will fill this gap by exploiting recent advances in genomics technology to sequence the entire transcriptome of the longest running study of wild birds – the great tit population in Wytham Woods, Oxford. Having identified most of the sequence variation in the great tit transcriptome, I will then genotype all birds for whom phenotype records and blood samples are available This will be, by far, the largest phenotype-genotype dataset of any free-living vertebrate population. I will then use gene mapping techniques to identify genes and genomic regions responsible for variation in a number of key traits such as lifetime recruitment, clutch size and breeding/laying date. This will result in a greater understanding, at the molecular level, how microevolutionary change can arise (or be constrained).
Max ERC Funding
1 560 770 €
Duration
Start date: 2008-10-01, End date: 2014-06-30
Project acronym CHROMOSOME STABILITY
Project Coordination of DNA replication and DNA repair at single-forks: the role of the Smc5-Smc6 complex in replication fork stalling and resumption
Researcher (PI) Luis Fernando Aragon Alcaide
Host Institution (HI) IMPERIAL COLLEGE OF SCIENCE TECHNOLOGY AND MEDICINE
Call Details Starting Grant (StG), LS1, ERC-2007-StG
Summary DNA replication represents a dangerous moment in the life of the cell as endogenous and exogenous events challenge genome integrity by interfering with the progression, stability and restart of the replication fork. Failure to protect stalled forks or to process the replication fork appropriately contribute to the pathological mechanisms giving rise to cancer, therefore an understanding of the intricate mechanisms that ensure fork integrity can provide targets for new chemotherapeutic assays. Smc5-Smc6 is a multi-subunit complex with a poorly understood function in DNA replication and repair. One of its subunits, Nse2, is able to promote the addition of a small ubiquitin-like protein modifier (SUMO) to specific target proteins. Recent work has revealed that the Smc5-Smc6 complex is required for the progression of replication forks through damaged DNA and is recruited de novo to forks that undergo collapse. In addition, Smc5-Smc6 mediate repair of DNA breaks by homologous recombination between sister-chromatids. Thus, Smc5-Smc6 is anticipated to promote recombinational repair at stalled/collapsed replication forks. My laboratory proposes to develop molecular techniques to study replication at the level of single replication forks. We will employ these assays to identify and dissect the function of factors involved in replication fork stability and repair. We will place an emphasis on the study of the Smc5-Smc6 complex in these processes because of its potential roles in recombination-dependent fork repair and restart. We also propose to identify novel Nse2 substrates involved in DNA repair using yeast model systems. Specifically, we will address the following points: (1) Development of assays for analysis of factors involved in stabilisation, collapse and re-start of single-forks, (2) Analysis of the roles of Smc5-Smc6 in fork biology using developed techniques, (3) Isolation and functional analysis of novel Nse2 substrates.
Summary
DNA replication represents a dangerous moment in the life of the cell as endogenous and exogenous events challenge genome integrity by interfering with the progression, stability and restart of the replication fork. Failure to protect stalled forks or to process the replication fork appropriately contribute to the pathological mechanisms giving rise to cancer, therefore an understanding of the intricate mechanisms that ensure fork integrity can provide targets for new chemotherapeutic assays. Smc5-Smc6 is a multi-subunit complex with a poorly understood function in DNA replication and repair. One of its subunits, Nse2, is able to promote the addition of a small ubiquitin-like protein modifier (SUMO) to specific target proteins. Recent work has revealed that the Smc5-Smc6 complex is required for the progression of replication forks through damaged DNA and is recruited de novo to forks that undergo collapse. In addition, Smc5-Smc6 mediate repair of DNA breaks by homologous recombination between sister-chromatids. Thus, Smc5-Smc6 is anticipated to promote recombinational repair at stalled/collapsed replication forks. My laboratory proposes to develop molecular techniques to study replication at the level of single replication forks. We will employ these assays to identify and dissect the function of factors involved in replication fork stability and repair. We will place an emphasis on the study of the Smc5-Smc6 complex in these processes because of its potential roles in recombination-dependent fork repair and restart. We also propose to identify novel Nse2 substrates involved in DNA repair using yeast model systems. Specifically, we will address the following points: (1) Development of assays for analysis of factors involved in stabilisation, collapse and re-start of single-forks, (2) Analysis of the roles of Smc5-Smc6 in fork biology using developed techniques, (3) Isolation and functional analysis of novel Nse2 substrates.
Max ERC Funding
893 396 €
Duration
Start date: 2008-09-01, End date: 2013-08-31
Project acronym CLIP
Project Mapping functional protein-RNA interactions to identify new targets for oligonucleotide-based therapy
Researcher (PI) Jernej Ule
Host Institution (HI) UNIVERSITY COLLEGE LONDON
Call Details Starting Grant (StG), LS1, ERC-2007-StG
Summary An important question of modern neurobiology is how neurons regulate synaptic function in response to excitation. In particular, the roles of alternative pre-mRNA splicing and mRNA translation regulation in this response are poorly understood. We will study the RNA-binding proteins (RBPs) that control these post-transcriptional changes using a UV crosslinking-based purification method (CLIP) and ultra-high throughput sequencing. Computational analysis of the resulting data will define the sequence and structural features of RNA motifs recognized by each RBP. Splicing microarrays and translation reporter assays will then allow us to examine the regulatory functions of RBPs and RNA motifs. By integrating the biochemical and functional datasets, we will relate the position of RNA motifs to the activity of bound RBPs, and predict the interactions that act as central nodes in the regulatory network. The physiological role of these core RBP-RNA interactions will then be tested using antisense RNAs. Together, these projects will provide insights to the regulatory mechanisms underlying neuronal activity-dependent changes, and provide new opportunities for future treatments of neurodegenerative disorders.
Summary
An important question of modern neurobiology is how neurons regulate synaptic function in response to excitation. In particular, the roles of alternative pre-mRNA splicing and mRNA translation regulation in this response are poorly understood. We will study the RNA-binding proteins (RBPs) that control these post-transcriptional changes using a UV crosslinking-based purification method (CLIP) and ultra-high throughput sequencing. Computational analysis of the resulting data will define the sequence and structural features of RNA motifs recognized by each RBP. Splicing microarrays and translation reporter assays will then allow us to examine the regulatory functions of RBPs and RNA motifs. By integrating the biochemical and functional datasets, we will relate the position of RNA motifs to the activity of bound RBPs, and predict the interactions that act as central nodes in the regulatory network. The physiological role of these core RBP-RNA interactions will then be tested using antisense RNAs. Together, these projects will provide insights to the regulatory mechanisms underlying neuronal activity-dependent changes, and provide new opportunities for future treatments of neurodegenerative disorders.
Max ERC Funding
900 000 €
Duration
Start date: 2008-09-01, End date: 2013-08-31
Project acronym CODING_IN_V1
Project How visual information is represented by neuronal networks in the primary visual cortex
Researcher (PI) Thomas D. Mrsic-Flogel
Host Institution (HI) UNIVERSITY COLLEGE LONDON
Call Details Starting Grant (StG), LS4, ERC-2007-StG
Summary The vast majority of our knowledge about how the brain encodes information has been obtained from recordings of one or few neurons at a time or from global mapping methods such as fMRI. These approaches have left unexplored how neuronal activity is distributed in space and time within a cortical column and how hundreds of neurons interact to process sensory information. By taking advantage of the most recent advances in two-photon microscopy, the proposed project addresses two broad aims, with a particular focus on the function and development of primary visual cortex: 1) to understand how cortical neuronal networks encode visual information, and 2) to understand how they become specialised for sensory processing during postnatal development. For the first aim, we will use in vivo two-photon calcium imaging to record activity simultaneously from hundreds of neurons in visual cortex while showing different visual stimuli to anaesthetised mice. This approach enables us for the first time to characterise in detail how individual neurons and neuronal subsets interact within a large cortical network in response to artificial and natural stimuli. Genetically-encoded fluorescent proteins expressed in distinct cell-types will inform us how excitatory and inhibitory neurons interact to shape population responses during vision. For the second aim, the same approach will be used to describe the maturation of cortical network function after the onset of vision and to assess the role of visual experience in this process. We will additionally use Channelrhodopsin-2, a genetic tool for remote control of action potential firing, to examine the role of correlated neuronal activity on establishment of functional cortical circuits. Together, this work will bring us closer to unravelling how sensory coding emerges on the level of neuronal networks.
Summary
The vast majority of our knowledge about how the brain encodes information has been obtained from recordings of one or few neurons at a time or from global mapping methods such as fMRI. These approaches have left unexplored how neuronal activity is distributed in space and time within a cortical column and how hundreds of neurons interact to process sensory information. By taking advantage of the most recent advances in two-photon microscopy, the proposed project addresses two broad aims, with a particular focus on the function and development of primary visual cortex: 1) to understand how cortical neuronal networks encode visual information, and 2) to understand how they become specialised for sensory processing during postnatal development. For the first aim, we will use in vivo two-photon calcium imaging to record activity simultaneously from hundreds of neurons in visual cortex while showing different visual stimuli to anaesthetised mice. This approach enables us for the first time to characterise in detail how individual neurons and neuronal subsets interact within a large cortical network in response to artificial and natural stimuli. Genetically-encoded fluorescent proteins expressed in distinct cell-types will inform us how excitatory and inhibitory neurons interact to shape population responses during vision. For the second aim, the same approach will be used to describe the maturation of cortical network function after the onset of vision and to assess the role of visual experience in this process. We will additionally use Channelrhodopsin-2, a genetic tool for remote control of action potential firing, to examine the role of correlated neuronal activity on establishment of functional cortical circuits. Together, this work will bring us closer to unravelling how sensory coding emerges on the level of neuronal networks.
Max ERC Funding
1 080 000 €
Duration
Start date: 2008-07-01, End date: 2013-06-30
Project acronym CONSERVREGCIRCUITRY
Project Conservation and Divergence of Tissue-Specific Transcriptional Regulation
Researcher (PI) Duncan Odom
Host Institution (HI) THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE
Call Details Starting Grant (StG), LS2, ERC-2007-StG
Summary Vertebrates contain hundreds of different cell types which maintain phenotypic identity by a combination of epigenetic programming and genomic regulation. Systems biology approaches are now used in a number of laboratories to determine how transcription factors and chromatin marks pattern the human genome. Despite high conservation of the cellular and molecular function of many mammalian transcription factors, our recent experiments in matched mouse and human tissues indicates that most transcription factor binding events to DNA are very poorly conserved. A hypothesis that could account for this apparent divergence is that the larger regional pattern of transcription factor binding may be conserved. To test this, (1) we are characterizing the global transcriptional profile, chromatin state, and complete genomic occupancy of a set of tissue-specific transcription factors in hepatocytes of strategically chosen mammals; (2) to further identify the precise mechanistic contribution of cis and trans effects, we are comparing transcription factor binding at homologous regions of human and mouse DNA in a mouse line that carries human chromosome 21. Together, these projects will provide insight into the general principles of how transcriptional networks are evolutionarily conserved to regulate cell fate specification and function using a clinically important cell type as a model.
Summary
Vertebrates contain hundreds of different cell types which maintain phenotypic identity by a combination of epigenetic programming and genomic regulation. Systems biology approaches are now used in a number of laboratories to determine how transcription factors and chromatin marks pattern the human genome. Despite high conservation of the cellular and molecular function of many mammalian transcription factors, our recent experiments in matched mouse and human tissues indicates that most transcription factor binding events to DNA are very poorly conserved. A hypothesis that could account for this apparent divergence is that the larger regional pattern of transcription factor binding may be conserved. To test this, (1) we are characterizing the global transcriptional profile, chromatin state, and complete genomic occupancy of a set of tissue-specific transcription factors in hepatocytes of strategically chosen mammals; (2) to further identify the precise mechanistic contribution of cis and trans effects, we are comparing transcription factor binding at homologous regions of human and mouse DNA in a mouse line that carries human chromosome 21. Together, these projects will provide insight into the general principles of how transcriptional networks are evolutionarily conserved to regulate cell fate specification and function using a clinically important cell type as a model.
Max ERC Funding
960 000 €
Duration
Start date: 2008-10-01, End date: 2013-09-30
Project acronym COSPSENA
Project Coherence of Spins in Semiconductor Nanostructures
Researcher (PI) Dominik Max Zumbühl
Host Institution (HI) UNIVERSITAT BASEL
Call Details Starting Grant (StG), PE3, ERC-2007-StG
Summary Macroscopic control of quantum states is a major theme in much of modern physics because quantum coherence enables study of fundamental physics and has promising applications for quantum information processing. The potential significance of quantum computing is recognized well beyond the physics community. For electron spins in GaAs quantum dots, it has become clear that decoherence caused by interactions with the nuclear spins is a major challenge. We propose to investigate and reduce hyperfine induced decoherence with two complementary approaches: nuclear spin state narrowing and nuclear spin polarization. We propose a new projective state narrowing technique: a large, Coulomb blockaded dot measures the qubit nuclear ensemble, resulting in enhanced spin coherence times. Further, mediated by an interacting 2D electron gas via hyperfine interaction, a low temperature nuclear ferromagnetic spin state was predicted, which we propose to investigate using a quantum point contact as a nuclear polarization detector. Estimates indicate that the nuclear ferromagnetic transition occurs in the sub-Millikelvin range, well below already hard to reach temperatures around 10 mK. However, the exciting combination of interacting electron and nuclear spin physics as well as applications in spin qubits give ample incentive to strive for sub-Millikelvin temperatures in nanostructures. We propose to build a novel type of nuclear demagnetization refrigerator aiming to reach electron temperatures of 0.1 mK in semiconductor nanostructures. This interdisciplinary project combines Microkelvin and nanophysics, going well beyond the status quo. It is a challenging project that could be the beginning of a new era of coherent spin physics with unprecedented quantum control. This project requires a several year commitment and a team of two graduate students plus one postdoctoral fellow.
Summary
Macroscopic control of quantum states is a major theme in much of modern physics because quantum coherence enables study of fundamental physics and has promising applications for quantum information processing. The potential significance of quantum computing is recognized well beyond the physics community. For electron spins in GaAs quantum dots, it has become clear that decoherence caused by interactions with the nuclear spins is a major challenge. We propose to investigate and reduce hyperfine induced decoherence with two complementary approaches: nuclear spin state narrowing and nuclear spin polarization. We propose a new projective state narrowing technique: a large, Coulomb blockaded dot measures the qubit nuclear ensemble, resulting in enhanced spin coherence times. Further, mediated by an interacting 2D electron gas via hyperfine interaction, a low temperature nuclear ferromagnetic spin state was predicted, which we propose to investigate using a quantum point contact as a nuclear polarization detector. Estimates indicate that the nuclear ferromagnetic transition occurs in the sub-Millikelvin range, well below already hard to reach temperatures around 10 mK. However, the exciting combination of interacting electron and nuclear spin physics as well as applications in spin qubits give ample incentive to strive for sub-Millikelvin temperatures in nanostructures. We propose to build a novel type of nuclear demagnetization refrigerator aiming to reach electron temperatures of 0.1 mK in semiconductor nanostructures. This interdisciplinary project combines Microkelvin and nanophysics, going well beyond the status quo. It is a challenging project that could be the beginning of a new era of coherent spin physics with unprecedented quantum control. This project requires a several year commitment and a team of two graduate students plus one postdoctoral fellow.
Max ERC Funding
1 377 000 €
Duration
Start date: 2008-06-01, End date: 2013-05-31
Project acronym DC-LYMPH
Project The Role of Lymphatic Vessels in Dendritic Cell Homing and Maturation
Researcher (PI) Melody A. Swartz
Host Institution (HI) ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE
Call Details Starting Grant (StG), LS3, ERC-2007-StG
Summary Dendritic cell (DC) activation and homing from the periphery to lymph nodes is a critical first event in the immune response. It involves upregulation of the chemokine receptor CCR7 and chemoinvasion towards lymphatic vessels. Despite its critical importance in adaptive immunity, the mechanisms of DC migration towards and entry into lymphatics are still poorly understood; this severely limits new therapeutic strategies for immunomodulation and even strategies for treating lymphedema, which is exacerbated by poor immune functioning. We propose a battery of physiological, cell-biological, molecular, and computational studies to determine both the mechanisms of DC homing to lymphatic vessels and how DCs modulate lymphatic function. We approach this from the perspectives of both the DC and the lymphatic vessel. Regarding the DC, we will examine computationally and experimentally how draining flows toward the lymphatic alter their migration tactics and test our hypothesis that DCs possess a biomolecular flow-detector network (which we refer to as autologous chemotaxis) and are thus able to sense the direction of the subtle flow of fluid toward the lymphatics. Regarding the lymphatic vessel, we will elucidate how biochemical and biophysical inflammatory signals regulate their drainage function, alter cell-cell adhesions and overall permeability, and alter adhesion receptors to facilitate DC homing and entry. Finally, we will examine DC migration in mice with dysfunctional lymphatics and explore strategies to improve immune response. These will be carried out in 4 main projects, and will complement our recent work in lymphatic functional biology as well as our more therapeutic investigations in DC targeting and activation (Reddy et al., Nature Biotechnol., 2007). This deeper knowledge of mechanisms of DC-lymphatic cross-talk in a relevant biophysical context will enable our long-term goal of rational design for therapeutic immunomodulation and lymphedema.
Summary
Dendritic cell (DC) activation and homing from the periphery to lymph nodes is a critical first event in the immune response. It involves upregulation of the chemokine receptor CCR7 and chemoinvasion towards lymphatic vessels. Despite its critical importance in adaptive immunity, the mechanisms of DC migration towards and entry into lymphatics are still poorly understood; this severely limits new therapeutic strategies for immunomodulation and even strategies for treating lymphedema, which is exacerbated by poor immune functioning. We propose a battery of physiological, cell-biological, molecular, and computational studies to determine both the mechanisms of DC homing to lymphatic vessels and how DCs modulate lymphatic function. We approach this from the perspectives of both the DC and the lymphatic vessel. Regarding the DC, we will examine computationally and experimentally how draining flows toward the lymphatic alter their migration tactics and test our hypothesis that DCs possess a biomolecular flow-detector network (which we refer to as autologous chemotaxis) and are thus able to sense the direction of the subtle flow of fluid toward the lymphatics. Regarding the lymphatic vessel, we will elucidate how biochemical and biophysical inflammatory signals regulate their drainage function, alter cell-cell adhesions and overall permeability, and alter adhesion receptors to facilitate DC homing and entry. Finally, we will examine DC migration in mice with dysfunctional lymphatics and explore strategies to improve immune response. These will be carried out in 4 main projects, and will complement our recent work in lymphatic functional biology as well as our more therapeutic investigations in DC targeting and activation (Reddy et al., Nature Biotechnol., 2007). This deeper knowledge of mechanisms of DC-lymphatic cross-talk in a relevant biophysical context will enable our long-term goal of rational design for therapeutic immunomodulation and lymphedema.
Max ERC Funding
1 730 966 €
Duration
Start date: 2008-05-01, End date: 2013-04-30
Project acronym DCBIF
Project Flight dynamics and control of birds and insects
Researcher (PI) Graham Keith Taylor
Host Institution (HI) THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
Call Details Starting Grant (StG), PE6, ERC-2007-StG
Summary Insects bristle with sensors, but how do they exploit this rich sensory information to achieve their extraordinary stability and manoeuvrability? Bird and insect wings deform in flight, and have passively deployable structures such as feathers and flaps, but how do they exploit these features when aircraft designers shy away from aeroelasticity? Birds fly without a vertical tailfin, but how do they maintain yaw stability when most aircraft require one to fly safely? Questions such as these drive my research on bird and insect flight dynamics. My research is unique in using the engineering tools of flight dynamics and control theory to analyse physiological and biomechanical data from real animals. One research track will use measurements of the forces and torques generated by insects flying tethered in a virtual-reality flight simulator to parameterise their equations of motion, in order to model the input-output relationships of their sensorimotor control systems. A second research track will measure the detailed wing kinematics and deformations of free-flying insects in order to analyse the effects of aeroelasticity on flight manoeuvres. A third research track will measure the wing and tail kinematics of free-flying birds using onboard wireless video cameras, and use system identification techniques to model how these affect the body dynamics measured using onboard instrumentation. Applying these novel experimental techniques will allow me to make and test quantitative predictions about flight stability and control. This highly interdisciplinary research bridges the fields of physiology and biomechanics, with significant feeds to and from engineering. My research will break new ground, developing novel experimental techniques and theoretical models in order to test and generate new hypotheses of adaptive function. Its broader impacts include the public interest in all things flying, and potential military and civilian applications in flapping micro-air vehicles.
Summary
Insects bristle with sensors, but how do they exploit this rich sensory information to achieve their extraordinary stability and manoeuvrability? Bird and insect wings deform in flight, and have passively deployable structures such as feathers and flaps, but how do they exploit these features when aircraft designers shy away from aeroelasticity? Birds fly without a vertical tailfin, but how do they maintain yaw stability when most aircraft require one to fly safely? Questions such as these drive my research on bird and insect flight dynamics. My research is unique in using the engineering tools of flight dynamics and control theory to analyse physiological and biomechanical data from real animals. One research track will use measurements of the forces and torques generated by insects flying tethered in a virtual-reality flight simulator to parameterise their equations of motion, in order to model the input-output relationships of their sensorimotor control systems. A second research track will measure the detailed wing kinematics and deformations of free-flying insects in order to analyse the effects of aeroelasticity on flight manoeuvres. A third research track will measure the wing and tail kinematics of free-flying birds using onboard wireless video cameras, and use system identification techniques to model how these affect the body dynamics measured using onboard instrumentation. Applying these novel experimental techniques will allow me to make and test quantitative predictions about flight stability and control. This highly interdisciplinary research bridges the fields of physiology and biomechanics, with significant feeds to and from engineering. My research will break new ground, developing novel experimental techniques and theoretical models in order to test and generate new hypotheses of adaptive function. Its broader impacts include the public interest in all things flying, and potential military and civilian applications in flapping micro-air vehicles.
Max ERC Funding
1 954 565 €
Duration
Start date: 2008-06-01, End date: 2014-05-31
