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Project acronym activeFly
Project Circuit mechanisms of self-movement estimation during walking
Researcher (PI) M Eugenia CHIAPPE
Host Institution (HI) FUNDACAO D. ANNA SOMMER CHAMPALIMAUD E DR. CARLOS MONTEZ CHAMPALIMAUD
Summary The brain evolves, develops, and operates in the context of animal movements. As a consequence, fundamental brain functions such as spatial perception and motor control critically depend on the precise knowledge of the ongoing body motion. An accurate internal estimate of self-movement is thought to emerge from sensorimotor integration; nonetheless, which circuits perform this internal estimation, and exactly how motor-sensory coordination is implemented within these circuits are basic questions that remain to be poorly understood. There is growing evidence suggesting that, during locomotion, motor-related and visual signals interact at early stages of visual processing. In mammals, however, it is not clear what the function of this interaction is. Recently, we have shown that a population of Drosophila optic-flow processing neurons —neurons that are sensitive to self-generated visual flow, receives convergent visual and walking-related signals to form a faithful representation of the fly's walking movements. Leveraging from these results, and combining quantitative analysis of behavior with physiology, optogenetics, and modelling, we propose to investigate circuit mechanisms of self-movement estimation during walking. We will:1) use cell specific manipulations to identify what cells are necessary to generate the motor-related activity in the population of visual neurons, 2) record from the identified neurons and correlate their activity with specific locomotor parameters, and 3) perturb the activity of different cell-types within the identified circuits to test their role in the dynamics of the visual neurons, and on the fly's walking behavior. These experiments will establish unprecedented causal relationships among neural activity, the formation of an internal representation, and locomotor control. The identified sensorimotor principles will establish a framework that can be tested in other scenarios or animal systems with implications both in health and disease.
The brain evolves, develops, and operates in the context of animal movements. As a consequence, fundamental brain functions such as spatial perception and motor control critically depend on the precise knowledge of the ongoing body motion. An accurate internal estimate of self-movement is thought to emerge from sensorimotor integration; nonetheless, which circuits perform this internal estimation, and exactly how motor-sensory coordination is implemented within these circuits are basic questions that remain to be poorly understood. There is growing evidence suggesting that, during locomotion, motor-related and visual signals interact at early stages of visual processing. In mammals, however, it is not clear what the function of this interaction is. Recently, we have shown that a population of Drosophila optic-flow processing neurons —neurons that are sensitive to self-generated visual flow, receives convergent visual and walking-related signals to form a faithful representation of the fly's walking movements. Leveraging from these results, and combining quantitative analysis of behavior with physiology, optogenetics, and modelling, we propose to investigate circuit mechanisms of self-movement estimation during walking. We will:1) use cell specific manipulations to identify what cells are necessary to generate the motor-related activity in the population of visual neurons, 2) record from the identified neurons and correlate their activity with specific locomotor parameters, and 3) perturb the activity of different cell-types within the identified circuits to test their role in the dynamics of the visual neurons, and on the fly's walking behavior. These experiments will establish unprecedented causal relationships among neural activity, the formation of an internal representation, and locomotor control. The identified sensorimotor principles will establish a framework that can be tested in other scenarios or animal systems with implications both in health and disease.
Project acronym AXIAL.EC
Project PRINCIPLES OF AXIAL POLARITY-DRIVEN VASCULAR PATTERNING
Researcher (PI) Claudio Franco
Host Institution (HI) INSTITUTO DE MEDICINA MOLECULAR JOAO LOBO ANTUNES
Summary The formation of a functional patterned vascular network is essential for development, tissue growth and organ physiology. Several human vascular disorders arise from the mis-patterning of blood vessels, such as arteriovenous malformations, aneurysms and diabetic retinopathy. Although blood flow is recognised as a stimulus for vascular patterning, very little is known about the molecular mechanisms that regulate endothelial cell behaviour in response to flow and promote vascular patterning. Recently, we uncovered that endothelial cells migrate extensively in the immature vascular network, and that endothelial cells polarise against the blood flow direction. Here, we put forward the hypothesis that vascular patterning is dependent on the polarisation and migration of endothelial cells against the flow direction, in a continuous flux of cells going from low-shear stress to high-shear stress regions. We will establish new reporter mouse lines to observe and manipulate endothelial polarity in vivo in order to investigate how polarisation and coordination of endothelial cells movements are orchestrated to generate vascular patterning. We will manipulate cell polarity using mouse models to understand the importance of cell polarisation in vascular patterning. Also, using a unique zebrafish line allowing analysis of endothelial cell polarity, we will perform a screen to identify novel regulators of vascular patterning. Finally, we will explore the hypothesis that defective flow-dependent endothelial polarisation underlies arteriovenous malformations using two genetic models. This integrative approach, based on high-resolution imaging and unique experimental models, will provide a unifying model defining the cellular and molecular principles involved in vascular patterning. Given the physiological relevance of vascular patterning in health and disease, this research plan will set the basis for the development of novel clinical therapies targeting vascular disorders.
The formation of a functional patterned vascular network is essential for development, tissue growth and organ physiology. Several human vascular disorders arise from the mis-patterning of blood vessels, such as arteriovenous malformations, aneurysms and diabetic retinopathy. Although blood flow is recognised as a stimulus for vascular patterning, very little is known about the molecular mechanisms that regulate endothelial cell behaviour in response to flow and promote vascular patterning. Recently, we uncovered that endothelial cells migrate extensively in the immature vascular network, and that endothelial cells polarise against the blood flow direction. Here, we put forward the hypothesis that vascular patterning is dependent on the polarisation and migration of endothelial cells against the flow direction, in a continuous flux of cells going from low-shear stress to high-shear stress regions. We will establish new reporter mouse lines to observe and manipulate endothelial polarity in vivo in order to investigate how polarisation and coordination of endothelial cells movements are orchestrated to generate vascular patterning. We will manipulate cell polarity using mouse models to understand the importance of cell polarisation in vascular patterning. Also, using a unique zebrafish line allowing analysis of endothelial cell polarity, we will perform a screen to identify novel regulators of vascular patterning. Finally, we will explore the hypothesis that defective flow-dependent endothelial polarisation underlies arteriovenous malformations using two genetic models. This integrative approach, based on high-resolution imaging and unique experimental models, will provide a unifying model defining the cellular and molecular principles involved in vascular patterning. Given the physiological relevance of vascular patterning in health and disease, this research plan will set the basis for the development of novel clinical therapies targeting vascular disorders.
Project acronym BUMP
Project BETTER UNDERSTANDING the METAPHYSICS of PREGNANCY
Researcher (PI) Elisabeth Marjolijn Kingma
Summary Every single human is the product of a pregnancy: an approximately nine-month period during which a foetus develops within its mother's body. Yet pregnancy has not been a traditional focus in philosophy. That is remarkable, for two reasons: First, because pregnancy presents fascinating philosophical problems: what, during the pregnancy, is the nature of the relationship between the foetus and the maternal organism? What is the relationship between the pregnant organism and the later baby? And when does one person or organism become two? Second, because so many topics immediately adjacent to or involved in pregnancy have taken centre stage in philosophical enquiry. Examples include questions about personhood, foetuses, personal identity and the self. This project launches the metaphysics of pregnancy as an important and fundamental area of philosophical research. The core aims of the project are: (1) to develop a philosophically sophisticated account of human pregnancy and birth, and the entities involved in this, that is attentive to our best empirical understanding of human reproductive biology; (2) to articulate the metaphysics of organisms, persons and selves in a way that acknowledges the details of how we come into existence; and (3) to start the process of rewriting the legal, social and moral language we use to classify ourselves and our actions, so that it is compatible with and can accommodate the nature of pregnancy. The project will investigate these questions in the context of a range of philosophical sub disciplines, including analytic metaphysics, philosophy of biology and feminist philosophy, and in close dialogue with our best empirical understanding of the life sciences – most notably physiology.
Every single human is the product of a pregnancy: an approximately nine-month period during which a foetus develops within its mother's body. Yet pregnancy has not been a traditional focus in philosophy. That is remarkable, for two reasons: First, because pregnancy presents fascinating philosophical problems: what, during the pregnancy, is the nature of the relationship between the foetus and the maternal organism? What is the relationship between the pregnant organism and the later baby? And when does one person or organism become two? Second, because so many topics immediately adjacent to or involved in pregnancy have taken centre stage in philosophical enquiry. Examples include questions about personhood, foetuses, personal identity and the self. This project launches the metaphysics of pregnancy as an important and fundamental area of philosophical research. The core aims of the project are: (1) to develop a philosophically sophisticated account of human pregnancy and birth, and the entities involved in this, that is attentive to our best empirical understanding of human reproductive biology; (2) to articulate the metaphysics of organisms, persons and selves in a way that acknowledges the details of how we come into existence; and (3) to start the process of rewriting the legal, social and moral language we use to classify ourselves and our actions, so that it is compatible with and can accommodate the nature of pregnancy. The project will investigate these questions in the context of a range of philosophical sub disciplines, including analytic metaphysics, philosophy of biology and feminist philosophy, and in close dialogue with our best empirical understanding of the life sciences – most notably physiology.
Project acronym CELL HORMONE
Project Bringing into focus the cellular dynamics of the plant growth hormone gibberellin
Researcher (PI) Alexander Morgan JONES
Summary During an organism's development it must integrate internal and external information. An example in plants, whose development stretches across their lifetime, is the coordination between environmental stimuli and endogenous cues on regulating the key hormone gibberellin (GA). The present challenge is to understand how these diverse signals influence GA levels and how GA signalling leads to diverse GA responses. This challenge is deepened by a fundamental problem in hormone research: the specific responses directed by a given hormone often depend on the cell-type, timing, and amount of hormone accumulation, but hormone concentrations are most often assessed at the organism or tissue level. Our approach, based on a novel optogenetic biosensor, GA Perception Sensor 1 (GPS1), brings the goal of high-resolution quantification of GA in vivo within reach. In plants expressing GPS1, we observe gradients of GA in elongating root and shoot tissues. We now aim to understand how a series of independently tunable enzymatic and transport activities combine to articulate the GA gradients that we observe. We further aim to discover the mechanisms by which endogenous and environmental signals regulate these GA enzymes and transporters. Finally, we aim to understand how one of these signals, light, regulates GA patterns to influence dynamic cell growth and organ behavior. Our overarching goal is a systems level understanding of the signal integration upstream and growth programming downstream of GA. The groundbreaking aspect of this proposal is our focus at the cellular level, and we are uniquely positioned to carry out our multidisciplinary aims involving biosensor engineering, innovative imaging, and multiscale modelling. We anticipate that the discoveries stemming from this project will provide the detailed understanding necessary to make strategic interventions into GA dynamic patterning in crop plants for specific improvements in growth, development, and environmental responses.
During an organism's development it must integrate internal and external information. An example in plants, whose development stretches across their lifetime, is the coordination between environmental stimuli and endogenous cues on regulating the key hormone gibberellin (GA). The present challenge is to understand how these diverse signals influence GA levels and how GA signalling leads to diverse GA responses. This challenge is deepened by a fundamental problem in hormone research: the specific responses directed by a given hormone often depend on the cell-type, timing, and amount of hormone accumulation, but hormone concentrations are most often assessed at the organism or tissue level. Our approach, based on a novel optogenetic biosensor, GA Perception Sensor 1 (GPS1), brings the goal of high-resolution quantification of GA in vivo within reach. In plants expressing GPS1, we observe gradients of GA in elongating root and shoot tissues. We now aim to understand how a series of independently tunable enzymatic and transport activities combine to articulate the GA gradients that we observe. We further aim to discover the mechanisms by which endogenous and environmental signals regulate these GA enzymes and transporters. Finally, we aim to understand how one of these signals, light, regulates GA patterns to influence dynamic cell growth and organ behavior. Our overarching goal is a systems level understanding of the signal integration upstream and growth programming downstream of GA. The groundbreaking aspect of this proposal is our focus at the cellular level, and we are uniquely positioned to carry out our multidisciplinary aims involving biosensor engineering, innovative imaging, and multiscale modelling. We anticipate that the discoveries stemming from this project will provide the detailed understanding necessary to make strategic interventions into GA dynamic patterning in crop plants for specific improvements in growth, development, and environmental responses.
Project acronym CerebralHominoids
Project Evolutionary biology of human and great ape brain development in cerebral organoids
Researcher (PI) Madeline LANCASTER
Host Institution (HI) UNITED KINGDOM RESEARCH AND INNOVATION
Summary Humans are endowed with a number of advanced cognitive abilities not seen in other species. So what allows the human brain to stand out from the rest in these capabilities? In general, the brains of primates, including humans, have more neurons per unit volume than other mammals. But humans are also in the fortunate position of having the largest of the primate brains, making the number of neurons in the human cerebral cortex greatly expanded. Thus, the difference seems to be a matter of quantity, not quality. My laboratory is interested in understanding how neuron number, and thus brain size, is determined in human brain development. The research proposed here is aimed at taking an evolutionary approach to this question and comparing brain development in an in vitro 3D model system, cerebral organoids. This method, which relies on self-organization from differentiating pluripotent stem cells, recapitulates remarkably well the endogenous developmental program of the human brain. Having previously established the brain organoid approach, and more recently improved upon it with the application of bioengineering, my laboratory is in a unique position to carry out functional studies of human brain development. I propose to use this approach to compare developing human brain tissue to that of other hominid species and tease apart unique features of human neural stem cells and progenitors that allow them to generate more neurons and therefore a greater cerebral cortical size. Furthermore, we will perform transcriptomic and functional screening to identify factors underlying this expansion, followed by careful genetic substitution to test the contributions of putative evolutionary changes. In this way, we will functionally test putative human evolutionary changes in a manner not previously possible.
Humans are endowed with a number of advanced cognitive abilities not seen in other species. So what allows the human brain to stand out from the rest in these capabilities? In general, the brains of primates, including humans, have more neurons per unit volume than other mammals. But humans are also in the fortunate position of having the largest of the primate brains, making the number of neurons in the human cerebral cortex greatly expanded. Thus, the difference seems to be a matter of quantity, not quality. My laboratory is interested in understanding how neuron number, and thus brain size, is determined in human brain development. The research proposed here is aimed at taking an evolutionary approach to this question and comparing brain development in an in vitro 3D model system, cerebral organoids. This method, which relies on self-organization from differentiating pluripotent stem cells, recapitulates remarkably well the endogenous developmental program of the human brain. Having previously established the brain organoid approach, and more recently improved upon it with the application of bioengineering, my laboratory is in a unique position to carry out functional studies of human brain development. I propose to use this approach to compare developing human brain tissue to that of other hominid species and tease apart unique features of human neural stem cells and progenitors that allow them to generate more neurons and therefore a greater cerebral cortical size. Furthermore, we will perform transcriptomic and functional screening to identify factors underlying this expansion, followed by careful genetic substitution to test the contributions of putative evolutionary changes. In this way, we will functionally test putative human evolutionary changes in a manner not previously possible.
Project acronym CFS modelling
Project Chromosomal Common Fragile Sites: Unravelling their biological functions and the basis of their instability
Researcher (PI) Andres Joaquin Lopez-Contreras
Summary Cancer and other diseases are driven by genomic alterations initiated by DNA breaks. Within our genomes, some regions are particularly prone to breakage, and these are known as common fragile sites (CFSs). CFSs are present in every person and are frequently sites of oncogenic chromosomal rearrangements. Intriguingly, despite their fragility, many CFSs are well conserved through evolution, suggesting that these regions have important physiological functions that remain elusive. My previous background in genome editing, proteomics and replication-born DNA damage has given me the tools to propose an ambitious and comprehensive plan that tackles fundamental questions on the biology of CFSs. First, we will perform a systematic analysis of the function of CFSs. Most of the CFSs contain very large genes, which has made technically difficult to dissect whether the CFS role is due to the locus itself or to the encoded gene product. However, the emergence of the CRISPR/Cas9 technology now enables the study of CFSs on a more systematic basis. We will pioneer the engineering of mammalian models harbouring large deletions at CFS loci to investigate their physiological functions at the cellular and organism levels. For those CFSs that contain genes, the cDNAs will be re-introduced at a distal locus. Using this strategy, we will be able to achieve the first comprehensive characterization of CFS roles. Second, we will develop novel targeted approaches to interrogate the chromatin-bound proteome of CFSs and its dynamics during DNA replication. Finally, and given that CFS fragility is influenced both by cell cycle checkpoints and dNTP availability, we will use mouse models to study the impact of ATR/CHK1 pathway and dNTP levels on CFS instability and cancer. Taken together, I propose an ambitious, yet feasible, project to functionally annotate and characterise these poorly understood regions of the human genome, with important potential implications for improving human health.
Cancer and other diseases are driven by genomic alterations initiated by DNA breaks. Within our genomes, some regions are particularly prone to breakage, and these are known as common fragile sites (CFSs). CFSs are present in every person and are frequently sites of oncogenic chromosomal rearrangements. Intriguingly, despite their fragility, many CFSs are well conserved through evolution, suggesting that these regions have important physiological functions that remain elusive. My previous background in genome editing, proteomics and replication-born DNA damage has given me the tools to propose an ambitious and comprehensive plan that tackles fundamental questions on the biology of CFSs. First, we will perform a systematic analysis of the function of CFSs. Most of the CFSs contain very large genes, which has made technically difficult to dissect whether the CFS role is due to the locus itself or to the encoded gene product. However, the emergence of the CRISPR/Cas9 technology now enables the study of CFSs on a more systematic basis. We will pioneer the engineering of mammalian models harbouring large deletions at CFS loci to investigate their physiological functions at the cellular and organism levels. For those CFSs that contain genes, the cDNAs will be re-introduced at a distal locus. Using this strategy, we will be able to achieve the first comprehensive characterization of CFS roles. Second, we will develop novel targeted approaches to interrogate the chromatin-bound proteome of CFSs and its dynamics during DNA replication. Finally, and given that CFS fragility is influenced both by cell cycle checkpoints and dNTP availability, we will use mouse models to study the impact of ATR/CHK1 pathway and dNTP levels on CFS instability and cancer. Taken together, I propose an ambitious, yet feasible, project to functionally annotate and characterise these poorly understood regions of the human genome, with important potential implications for improving human health.
Project acronym CHIPS
Project Effects of Prenatal Exposure to Acrylamide on Health: Prospective Biomarker-Based Studies
Researcher (PI) Marie Pedersen
Summary Background: Acrylamide is a chemical formed in many commonly consumed foods and beverages. It is neurotoxic, crosses the placenta and has been associated with restriction of fetal growth in humans. In animals, acrylamide causes heritable mutations, tumors, developmental toxicity, reduced fertility and impaired growth. Therefore, the discovery of acrylamide in food in 2002 raised concern about human health effects worldwide. Still, epidemiological studies are limited and effects on health of prenatal exposure have never been evaluated. Research gaps: Epidemiological studies have mostly addressed exposure during adulthood, focused on cancer risk in adults, and relied on questionnaires entailing a high degree of exposure misclassification. Biomarker studies on prenatal exposure to acrylamide from diet are critically needed to improve exposure assessment and to determine whether acrylamide leads to major diseases later in life. Own results: I have first authored a prospective European study showing that prenatal exposure to acrylamide, estimated by measuring hemoglobin adducts in cord blood, was associated with fetal growth restriction, for the first time. Objectives: To determine the effects of prenatal exposure to acrylamide alone and in combination with other potentially toxic adduct-forming exposures on the health of children and young adults. Methods: Both well-established and innovative biomarker methods will be used for characterization of prenatal exposure to acrylamide and related toxicants in blood from pregnant women and their offspring in prospective cohort studies with long-term follow-up. Risk of neurological disorders, impaired cognition, disturbed reproductive function and metabolic outcomes such as obesity and diabetes will be evaluated. Perspectives: CHIPS project will provide a better understanding of the impact of prenatal exposure to acrylamide from diet on human health urgently needed for targeted strategies for the protection of the health.
Background: Acrylamide is a chemical formed in many commonly consumed foods and beverages. It is neurotoxic, crosses the placenta and has been associated with restriction of fetal growth in humans. In animals, acrylamide causes heritable mutations, tumors, developmental toxicity, reduced fertility and impaired growth. Therefore, the discovery of acrylamide in food in 2002 raised concern about human health effects worldwide. Still, epidemiological studies are limited and effects on health of prenatal exposure have never been evaluated. Research gaps: Epidemiological studies have mostly addressed exposure during adulthood, focused on cancer risk in adults, and relied on questionnaires entailing a high degree of exposure misclassification. Biomarker studies on prenatal exposure to acrylamide from diet are critically needed to improve exposure assessment and to determine whether acrylamide leads to major diseases later in life. Own results: I have first authored a prospective European study showing that prenatal exposure to acrylamide, estimated by measuring hemoglobin adducts in cord blood, was associated with fetal growth restriction, for the first time. Objectives: To determine the effects of prenatal exposure to acrylamide alone and in combination with other potentially toxic adduct-forming exposures on the health of children and young adults. Methods: Both well-established and innovative biomarker methods will be used for characterization of prenatal exposure to acrylamide and related toxicants in blood from pregnant women and their offspring in prospective cohort studies with long-term follow-up. Risk of neurological disorders, impaired cognition, disturbed reproductive function and metabolic outcomes such as obesity and diabetes will be evaluated. Perspectives: CHIPS project will provide a better understanding of the impact of prenatal exposure to acrylamide from diet on human health urgently needed for targeted strategies for the protection of the health.
Project acronym CREWS
Project Contexts of and Relations between Early Writing Systems
Researcher (PI) Philippa Mary Steele
Summary Contexts of and Relations between Early Writing Systems This project takes an innovative and interdisciplinary approach to the history of writing, redressing lingering problems that have hampered previous research and developing new methodologies for studying scripts and their social context. The staff on the project will work on specific case studies relating to inscriptions of the ancient Aegean, Eastern Mediterranean and Levant (c.2000-600 BC), developing a new and much deeper understanding of writing, literacy and social and cultural interrelations in the area than has ever been possible via the often out-dated traditional methods usually applied to these data. The focus will be on enriching our understanding of both linguistic and social aspects of the borrowing and propagation of writing. This planned research has the potential to change the way we think about writing systems, their societal context and the ways in which ideas were exchanged in early civilisations. Published and publicised through multiple outputs and media, the results will be of importance not only to the specific chronological period and geographical area under close consideration but also to the diachronic study of relationships between population groups and the significance of such relationships for the wider field of cultural history.
Contexts of and Relations between Early Writing Systems This project takes an innovative and interdisciplinary approach to the history of writing, redressing lingering problems that have hampered previous research and developing new methodologies for studying scripts and their social context. The staff on the project will work on specific case studies relating to inscriptions of the ancient Aegean, Eastern Mediterranean and Levant (c.2000-600 BC), developing a new and much deeper understanding of writing, literacy and social and cultural interrelations in the area than has ever been possible via the often out-dated traditional methods usually applied to these data. The focus will be on enriching our understanding of both linguistic and social aspects of the borrowing and propagation of writing. This planned research has the potential to change the way we think about writing systems, their societal context and the ways in which ideas were exchanged in early civilisations. Published and publicised through multiple outputs and media, the results will be of importance not only to the specific chronological period and geographical area under close consideration but also to the diachronic study of relationships between population groups and the significance of such relationships for the wider field of cultural history.
Project acronym ELEVATE
Project Eco-physiological tradeoffs with crop domestication: have farming ants cracked the code?
Researcher (PI) Jonathan Zvi SHIK
Summary Domesticated crops hardly resemble their wild ancestors, and often trade higher yield in artificially optimized conditions for lower performance in fluctuating environments. Leafcutter ants (genus Atta) provide fascinating parallels with human farmers, harvesting fresh vegetation used as compost to produce domesticated fungal crops that feed massive societies with millions of workers. However, while human agricultural systems are imperiled by rapid global changes, leafcutter ants have managed to grow one type of cultivar from Texas to Argentina, thriving across extreme rainfall and temperature gradients and across diverse climates over millions of years. However, the eco-physiological mechanisms governing this farming resiliency are poorly understood. I propose a new in vitro mapping paradigm to visualize the niche requirements of fungal cultivars. Creating multidimensional landscapes of nutrient availability (e.g. protein, carbohydrates, Na, P) and environmental stress (e.g. temperature, moisture, plant toxins, crop pathogens) I will answer three main questions: 1)	What genes and biochemical pathways shape cultivar performance across interacting gradients of nutrition and stress? 2)	Do colonies harvest substrates to navigate nutritional contours of cultivar performance maps and avoid production tradeoffs? 3)	Do locally adaptive cultivar traits shape the performance of farming societies across regional ecological gradients, and over 60 million years of co-evolutionary crop domestication by farming ants? My cutting-edge approach will deliver transformative advances to the field of eco-physiology, enabling seamless integration between field and laboratory experiments, and providing new ways to visualize evolutionary mechanisms across levels of biological organization from genes to symbiotic partnerships, and from within diverse farming assemblages to across populations spanning entire continents.
Domesticated crops hardly resemble their wild ancestors, and often trade higher yield in artificially optimized conditions for lower performance in fluctuating environments. Leafcutter ants (genus Atta) provide fascinating parallels with human farmers, harvesting fresh vegetation used as compost to produce domesticated fungal crops that feed massive societies with millions of workers. However, while human agricultural systems are imperiled by rapid global changes, leafcutter ants have managed to grow one type of cultivar from Texas to Argentina, thriving across extreme rainfall and temperature gradients and across diverse climates over millions of years. However, the eco-physiological mechanisms governing this farming resiliency are poorly understood. I propose a new in vitro mapping paradigm to visualize the niche requirements of fungal cultivars. Creating multidimensional landscapes of nutrient availability (e.g. protein, carbohydrates, Na, P) and environmental stress (e.g. temperature, moisture, plant toxins, crop pathogens) I will answer three main questions: 1)	What genes and biochemical pathways shape cultivar performance across interacting gradients of nutrition and stress? 2)	Do colonies harvest substrates to navigate nutritional contours of cultivar performance maps and avoid production tradeoffs? 3)	Do locally adaptive cultivar traits shape the performance of farming societies across regional ecological gradients, and over 60 million years of co-evolutionary crop domestication by farming ants? My cutting-edge approach will deliver transformative advances to the field of eco-physiology, enabling seamless integration between field and laboratory experiments, and providing new ways to visualize evolutionary mechanisms across levels of biological organization from genes to symbiotic partnerships, and from within diverse farming assemblages to across populations spanning entire continents.
Project acronym EPITOOLS
Project Chemical biology approaches to unraveling the histone code
Researcher (PI) Akane Kawamura
Summary Posttranslational modifications on histones play crucial roles in the epigenetic regulation of eukaryotic gene expression. Chemical modifications that occur on histone tails include acetylation, methylation, phosphorylation, ubiquitination, and SUMOylation. This chemical diversity together with the positions and combinations of these modifications give rise to complex networks of highly controlled gene expression programs. The identification and characterisation of chromatin-associated proteins (or epigenetic regulators) in recent years has advanced our understanding of the significance of these histone modifications and the regulatory outcomes in development and in disease. The project aims to generate new classes of highly selective and potent chemical probes for epigenetic regulators, focusing on enzymes and proteins associated with methyl-lysine marks. A novel modified peptide-based discovery platform, which combines molecular, chemical, biophysical and cellular techniques, will be developed and applied. These chemical probes will be useful for biological and biomedical research, and will serve as potential starting points for therapeutic epigenetic intervention.
Posttranslational modifications on histones play crucial roles in the epigenetic regulation of eukaryotic gene expression. Chemical modifications that occur on histone tails include acetylation, methylation, phosphorylation, ubiquitination, and SUMOylation. This chemical diversity together with the positions and combinations of these modifications give rise to complex networks of highly controlled gene expression programs. The identification and characterisation of chromatin-associated proteins (or epigenetic regulators) in recent years has advanced our understanding of the significance of these histone modifications and the regulatory outcomes in development and in disease. The project aims to generate new classes of highly selective and potent chemical probes for epigenetic regulators, focusing on enzymes and proteins associated with methyl-lysine marks. A novel modified peptide-based discovery platform, which combines molecular, chemical, biophysical and cellular techniques, will be developed and applied. These chemical probes will be useful for biological and biomedical research, and will serve as potential starting points for therapeutic epigenetic intervention.