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Funding
Funding
HFSP supports novel, innovative and interdisciplinary basic research focused on the complex mechanisms of living organisms. A clear emphasis is placed on novel collaborations that bring biologists together to focus on problems at the frontier of the life sciences.
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Awardees
Awardees
In this section you find information about the awardees in the HFSP scientific programs. This includes a searchable database of HFSP awardees, information on the HFSP Nakasone Award and other achievements by HFSP awardees.
- News & Impact
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Events
Events
HFSP promotes and participates in several events every year. We are committed to bringing together the scientific community and forging new opportunities to network and have scientific discussions that help to create bridges and partnerships for the future of frontier science.
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About
About
The Human Frontier Science Program is a program of funding for frontier research in the life sciences. It is implemented by the International Human Frontier Science Program Organization (HFSPO) with its office in Strasbourg. Here you can find all you need to know about the HFSPO.
Awardees
2022
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Long-Term Fellowships - LTF
Symmetry breaking in multicellular self-organization: a quantitative imaging approach
DUNSING Valentin (.)
. - DELEGATION CNRS PROVENCE ET CORSE - MARSEILLE - FRANCE
LENNE Pierre-Francois (Host supervisor)
Understanding the establishment of a body plan is an important challenge in biology. Progress in the field has been limited by a lack of approaches to understand multicellular tissue organization from first principles. I plan to study the first steps in mammalian development, when cell differentiation and multicellular organization establish the body axes during gastrulation. My goal is to elucidate how long range signaling cues such as morphogens and local cell-cell interactions generate tissue scale organization. As a model for primary axis formation, I will employ gastruloids, aggregates of mouse embryonic stem cells mimicking early mammalian embryos, and focus on the process of symmetry breaking, i.e. polarization of an initially homogeneous aggregate of equivalent cells. I will develop an original multiview light-sheet microscope to image multiple gastruloids live in 3D over several days with cellular resolution. I will track cells in 3D to explore 1) how signaling and differentiation propagate between individual cells; 2) how fate impacts on cell mechanics, motility and cell-cell contact dynamics. I will then apply chemical and mechanical perturbations to determine how these processes induce symmetry breaking. Finally, I will explore how robustness is achieved by monitoring symmetry breaking in aggregates of different sizes generated by global or local induction of cell differentiation. I will integrate the generated data into a mechanistic model to predict how biochemical and mechanical interactions generate tissue-scale patterning. This will provide unprecedented insights into multicellular self-organization relevant for development and regenerative medicine.
2022
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Long-Term Fellowships - LTF
Functional proteome landscape of malaria parasite during the life cycle in host and vector
DZIEKAN Jerzy (.)
. - Walter and Eliza Hall Institute of Medical Research - Parkville, Victoria - AUSTRALIA
COWMAN Alan (Host supervisor)
To achieve the ultimate goal of malaria elimination, a new generation of antimalarial therapeutics is required that have both transmission-blocking and chemoprotective properties. However, to facilitate the rational design of multi-stage targeting antimalarial drugs, we first need to bridge knowledge gaps in our understanding of malaria parasite transmission to mosquitoes and its development at the host-vector interface. Here, we will leverage two recently developed, powerful proteomic approaches, Thermal Proteome Profiling (TPP) and Limited Proteolysis Mass Spectrometry (Lip-MS), to characterise functional proteome states during malaria parasite sexual development in the host and the vector. TPP and Lip-MS allow proteome-wide readout of protein stability, which is influenced by protein interactions with diverse physiological ligands, metabolites, cofactors, DNA/RNA, posttranslational modifications and protein complex formation. Consequently, protein stability serves as a proxy for its functional state in a living cell. Monitoring stability dynamics can inform on the functional states of transcription factors, protein-protein interactions and enzyme activity. Datasets generated by this study will answer fundamental biological questions on proteome regulation during parasite development and the molecular events governing transmission. To characterise essential molecular processes, we will monitor the effect transmission-blocking agents on proteome stability, identifying their targets and pathways they disrupt. This project will not only develop a new understanding of malaria biology but will also identify novel avenues for the rational design of antimalarial interventions.
2022
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Long-Term Fellowships - LTF
Monitoring and manipulating inter-organellar contact-sites during mycobacterial infection
EISENBERG-BORD Michal (.)
. - University of Cambridge - Cambridge - United Kingdom
RAMAKRISHNAN Lalita (Host supervisor)
Tuberculosis (TB), humanity’s greatest infectious killer, kills nearly 2 million people a year with antibiotic resistance burgeoning. Understanding its fundamental pathogenesis could yield new treatments that overcome drug resistance by targeting host determinants and pathways that Mycobacterium tuberculosis (Mtb) exploits. Mtb first resides in macrophage phagosomes and phagolysosomes, then promotes macrophage necrosis, a critical pathogenic event that increases morbidity and transmission. Work in the zebrafish larval model of TB identified a macrophage necrosis pathway that requires transfer of molecules between mitochondria and lysosomes, and ER and mitochondria. I hypothesize Mtb manipulates interorganellar contact-sites to mediate pathogenesis—first intramacrophage growth and then macrophage necrosis through the newly-identified pathway. The transparent zebrafish larva is ideal to test this. I will determine which contact-sites are altered in infection using fluorescence-labeling tools and test their roles using CRISPR-Cas9 technologies. My work could lead to fundamental discoveries about both TB pathogenesis and contact-site biology while identifying potential new therapeutics. Later, I will expand to decipher the role of interorganellar contacts in other serious intracellular bacterial pathogens. My research will bring new ideas and approaches to infectious diseases pathogenesis. While acquiring training in this new area, I will bring my expertise in cell biology and interorganellar contact-sites to my mentor lab and my new field. Expertise that I acquire in the zebrafish model will provide me new toolkits to approach cell biological questions broadly in the future.
2022
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Long-Term Fellowships - LTF
Dissecting the structure-function consequences of mechanical stress on intact neural circuits
EL-QUESSNY Malak (.)
. - ICFO – The Institute of Photonic Sciences - Castelldefels - SPAIN
KRIEG Michael (Host supervisor)
Traumatic brain injuries (TBI), induced by strain or mechanical compression, compromise gross brain vasculature and signaling. On a cellular level, TBI has been shown to disrupt excitatory signaling as well as altering cellular morphology and the axonal cytoskeleton, which are now used as early indicators of progressive neurodegenerative diseases such as Alzheimer’s and Parkinson’s. Although the clinical importance of neuronal injury is widely recognized, a complete understanding of how mechanical forces influence the changes in neural structure and signaling remains unknown.
In this proposal, I develop a novel method for understanding the structure-function consequences of mechanical stresses, on intact mouse cerebral organoids, to study how neural circuits respond to injury. To do this, I will utilize a mouse line that stochastically expresses different fluorescent reporters, one of which is a genetically encoded calcium indicator (GCaMP), and culture their embryonic stem cells to form three-dimensional cerebral organoids (Lancaster et al 2013), yielding a “brainbow” inspired multicolor toolbox (Cai et al. 2013). Next, I will use a light sheet microscope (Huiskin et al. 2004) fitted with a microfluidic and mechanical confiner (Venturini et al. 2020) to probe the three-dimensional morphology of fluorescently labeled single neurons, their calcium responses to mechanical stresses, as well as the functional dynamics across organoid networks. With these tools, I can uncover the mechanism by which biomechanical stimuli influence the structure and function of mammalian circuits following injury and the cellular underpinnings of their subsequent degeneration.
2022
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Grant Awardees - Program
Bridging biophysics and evolution: impact of intermediate filament evolution on tissue mechanics
TOMANCAK Pavel (CZECH REPUBLIC)
Max Planck Institute of Molecular Cell Biology and Genetics - Max Planck Society - Dresden - GERMANY
HEISENBERG Carl-Philipp (GERMANY)
Heisenberg Lab - IST Austria - Klosterneuburg - AUSTRIA
HEJNOL Andreas (GERMANY)
Department of Biologial Sciences/Comparative Developmental Biology - Friedrich Schiller University Jena - Jena - GERMANY
EXTAVOUR Cassandra (CANADA)
Dept. of Organismic and Evolutionary Biology - Harvard University - Cambridge - USA
Interactions between mechanical and biochemical processes determine the shape of living matter. However, we do not understand how this interaction evolves to give rise to the large diversity of shapes of life. Our team will take a comparative approach at the interface between evolutionary developmental biology and biophysics to identify conserved and divergent mechanochemical interaction principles determining animal shape. Specifically, we will elucidate how the biochemical evolution of intermediate filaments (IFs) impacts the mechanical and morphogenetic properties of epithelial tissues undergoing spreading in different model and non-model organisms across the tree of life. Epithelial spreading, whereby a sheet of connected cells stretches to increase its surface area, is a common phenomenon in various developmental and disease-related processes, such as gastrulation, oogenesis and wound healing. IFs are generally thought to function in this process by providing epithelia with mechanical support, and to protect them from damage by external and internal forces. Our preliminary observations suggest that different mechanical properties of spreading epithelia in arthropods and vertebrates are associated to the presence of IFs in vertebrates, and their loss in arthropods. We thus hypothesize that the diversification of IFs is responsible for the evolution of species-specific mechanical properties of epithelial tissues determining their spreading behavior. We will test this hypothesis by strategically sampling species across animal phylogeny and determine how changes in IF biochemistry cause changes in epithelial mechanics and spreading. Finally, we will challenge this hypothesis by ambitious experiments where entire IF molecular machineries will be added to the genomes that do not have it, and examine the impact on epithelial tissue mechanics and morphogenesis. Our major innovation is bridging evolutionary biology and tissue biomechanics. This transdisciplinary approach will elucidate the physical basis for the genotype-phenotype relationship, revealing how mechanochemical processes evolve to yield diverse animal shapes. Our proposal combines the strengths of traditionally separate disciplines to investigate the morphogenetic role of IFs, central yet understudied cytoskeletal elements, across phylogeny.
2022
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Grant Awardees - Early Career
How fishes use historical hydrodynamic motion cues in search and navigation tasks
HERBERT-READ James (UK)
Department of Zoology - University of Cambridge - Cambridge - UK
FAN Dixia (CHINA, PEOPLE'S REPUBLIC OF)
Dept. of Sustainable and Environmental Engineering - Westlake University - Hangzhou - CHINA, PEOPLE'S REPUBLIC OF
JODIN Gurvan (FRANCE)
SATIE CNRS - ENS Rennes - BRUZ - FRANCE
Just as boats leave a wake as they travel over the surface of the water, underwater animals also leave a trail of water disturbance as they move through their environment. These trails, termed ‘hydrodynamic motion cues’, hold information about the size of the animal that was travelling through that location in the past, what type of animal it was, and how that animal was moving. In effect, these hydrodynamic motion cues represent a ‘liquid fingerprint’, holding information about the animal itself and and how it was travelling through that location in the past. Many species of fishes are able to detect the hydrodynamic pressure of these liquid fingerprint, however, we know little about how the hydrodynamic information detected by animals is used in their behavioural decision-making. In this project, we will test whether fishes that sense the hydrodynamic cues generated from the past movements of other animals use this information in different behavioural tasks. For example, some prey fishes may use these cues to find other group members, while other predatory species may use these cues to track their prey. Using a combination of behavioural experiments, modern sensing technology, and machine learning techniques, this project aims to understand how hydrodynamic motion cues are used by fishes in search and navigation tasks. This work will not only allow us to understand some of the extraordinary sensory and behavioral adaptations that animals have evolved in underwater environments, but will also be informative for engineering applications, including the design of autonomous sensing vehicles.
2022
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Grant Awardees - Program
The evolution of sperm cell shape and motion
HUMPHRIES Stuart (UK)
Physical Ecology lab., College of Science, School of Life Sciences - Lincoln Institute for Advanced Studies - Lincoln - UK
SNOOK Rhonda (USA)
Dept. of Zoology - Stockholm University - Stockholm - SWEDEN
FAUCI Lisa (USA)
Dept. of Mathematics - Tulane University - New Orleans - USA
Across the tree of life, sperm show an unrivalled diversity of shapes and sizes greater than any other cell type. The reasons for such diversity remain elusive. Most work has focussed on simple sperm shape found in externally fertilizing invertebrates and internally fertilizing vertebrates, yet most diversity is found in internally fertilizing invertebrates, especially insects. Therefore to truly understand how and why different sperm shapes have evolved, we need to shift away from these historically studied animals and focus on the evolution of insect sperm. In this project we will test how sperm shape and size variation has evolved and more specifically, how it allows sperm to perform their ultimate function – fertilisation. To do so, we will unite researchers from three differing disciplines: biophysics, evolutionary ecology, and mathematics. A biophysics approach will allow us to test how the sperm swim, and determine how the reproductive fluid and reproductive tracts they move in shape these movements. An evolutionary ecology focus will allow us to test how both large- and small-scale evolutionary variation in sperm shape is linked to coevolution with the fertilization environment of the female. The fundamental integration of mathematics across and within our projects will provide synthesis of empirical work and generate new predictions of how the combination of sperm shape and motion, reproductive tract structure, and competition between multiple sperm affect reproductive performance. Only by combining these three disciplines can we truly understand this sperm diversity for the first time. Novel experimental devices, microscale measurements of fluid properties, genetic studies and computational modelling will allow us to chart the evolution of sperm shape, understand how sperm form and female reproductive tracts evolved together, and to link all of these to predict and understand how sperm performance is determined.
2022
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Grant Awardees - Early Career
Reconstructing water to land transitions in arthropod evolution combining atoms, genes and fossils
FERNANDEZ Rosa (SPAIN)
CSIC - Institute of Evolutionary Biology - Barcelona - SPAIN
MUÑOZ-GARCIA Ana Belen (SPAIN)
Department of Physics "Ettore Pancini" - University of Naples Federico II - Naples - ITALY
ORTEGA-HERNANDEZ Javier (MEXICO)
Department of Organismic and Evolutionary Biology - Harvard University - Cambridge - USA
Breathing has played a key role in all animal life since its origins more than half a billion years ago. Animals occupy all types of environments, ranging from mountain tops to the bottom of the oceans. Despite this enormous variability of lifestyles, all animals fall within one of three possible categories for breathing: those that breathe air, those that breathe underwater, or those that do a combination of both. The common denominator is that all animals breathe to consume oxygen, a chemical element that can either be a lethal toxin or a vital gas, depending on the circumstances. The transition from breathing underwater to breathing air represents one of the most important steps in animal evolution, as it allowed them to explore dry land for the first time approximately 420 million years ago. However, the precise mechanisms responsible for the water to air transition of breathing and oxygen consumption remain largely unknown due to the complexity of this drastic change in the mode of life of early animals. The objective of this project is to investigate the early evolution of air-breathing among arthropods, animals with jointed legs whose living representatives include arachnids, millipedes, crustaceans and insects. Arthropods represent ideal case studies because they are among the first animals that evolved air-breathing as informed by the fossil record, as well as having well-developed structures for oxygen exchange such as external and internal gills. To better understand how animals acquired the capacity to consume oxygen from breathing air, we will explore this question from three interdisciplinary approaches: 1) We will explore how hemocyanins (the respiratory pigments of arthropods) have evolved through time and will investigate if the oxygen-transporting function in different respiratory structures is due to similar or different genes. 2) We will use the excellent fossil record of arthropods to investigate how respiratory structures have changed over millions of years, from fully marine animals during the Cambrian Explosion, to the first land-dwelling species that show the earliest evidence of adaptations for air-breathing in the Silurian and Devonian. 3) We will use and develop micro- and macroscopic physico-chemical approaches to investigate hemocyanin reactivity and respiratory flux features for different respiratory architectures.
2022
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Long-Term Fellowships - LTF
Dynamic threat assessment and signal integration by innate immune signaling complexes
FISCH Daniel (.)
. - Boston Children's Hospital - Boston - United States
KAGAN Jonathan (Host supervisor)
Pattern-recognition receptors (PRRs) of the innate immune system sense threats arising from pathogens or tissue injury, respectively known as pathogen or damage-associated molecular patterns (PAMPs/DAMPs). Upon activation, PRRs induce formation of supramolecular organizing centers (SMOCs). SMOCs are the signaling organelles of the innate immune system controlling cytokine production and cell death. SMOC activities were commonly studied in reductionist systems, using pure ligands of individual PRRs. However, during microbial encounters multiple PAMPs are present and likely contribute to SMOC activity, raising the possibility of additive, synergistic or even antagonism responses.
To test this, I propose to examine the dynamics of SMOC formation, composition, localization and effector activities using a distinct model system to prior approaches. Specifically, I plan to create CRISPR knock-in macrophages for live cell imaging and spatial proteomics. To offer modularity for PRR stimulation, I plan to use beads as “minimalist microbes”. Their regular, circular shape (and isolation methods for bead-containing phagosomes) allows monitoring protein localization and activities on these minimalist microbes. Combined with the flexibility to attach defined PAMPs, I envision development of a powerful discovery platform. Findings from these synthetic approaches will be scrutinized using primary cells to understand how SMOC assembly with defined ligands in isolation or in combination controls signaling and effector functions. This work will help elucidate how innate immune cells perceive and compute threats in an inflammatory environment and how they decide on an appropriate response.
2022
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Grant Awardees - Program
Multi-omic reconstruction of flow across the distributed metabolism of early-branching Dracula ants
LEBOEUF Adria (USA)
Department of Biology - University of Fribourg - Fribourg - SWITZERLAND
FISHER Brian Lee (USA)
Entomology - California Academy of Sciences - San Francisco - USA
TEUSINK Bas (NETHERLANDS)
Amsterdam Institute of Molecular and Life Science (AIMMS) - VU University Amsterdam - Amsterdam - NETHERLANDS
Many successes in life are based on collaboration – this extends to the molecular level, where life is fueled by the chemical processes collectively called metabolism. Microorganisms exchange nutrients through cross-feeding, and multicellular organisms are made up of tissues with different metabolic roles and needs. Social insects, where the notion of self is distributed over multiple individuals, take this collaboration still further: Many ant colonies engage in social exchanges of experimentally accessible fluids that contain both exogenously sourced and endogenously produced materials. Larvae of many social insects have been purported to be a ‘digestive caste.’ They are fed exogenously sourced food by adults and return a nutritious fluid whose metabolic functions remain unestablished. The mode of transmission from larvae to adults varies across ant species: In some, larvae voluntarily secrete fluids, while in early-branching ‘Dracula’ ants, adults non-destructively drink larval hemolymph. Such socially exchanged fluids can be analysed to monitor the fluxes of distributed metabolism, making ant colonies apt model systems to study the molecular mechanisms of inter-system communication and division of metabolic labor. We address three key questions (i) what is being exchanged? (ii) what are the functional implications of these exchanges? and (iii) how did these modes of exchange evolve? We combine behavior observations with detailed molecular analyses of four species representing different social feeding modes and evolutionary lineages. We perform proteomics and metabolomics on each colony-tissue and exchanged fluid. Based on genomes and gene expression, we reconstruct metabolic networks for advanced multi-omic data integration to identify active pathways. Novel community-scale metabolic modeling will be used to probe colony-level functionality of social exchange. Critical pathways will be validated with fluorescent metabolite probes in an automated colony- and transmission-tracking system and by genetic or feeding perturbations. This project offers new ways to view social behavior, evolutionary biology, metabolism and the physics of collective behavior. Ultimately, this work will innovate by elucidating the functional role of distributed metabolism, probing its evolution, and providing new tools to study community-level metabolic interactions.
2022
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Long-Term Fellowships - LTF
Dopaminergic basis of learning temporal regularities in perceptual decisions
FRITSCHE Matthias (.)
. - University of Oxford - Oxford - United Kingdom
LAK Armin (Host supervisor)
Learning from past decisions and their outcomes allows us to make predictions about the future, thereby improving subsequent decisions. Some predictions are formed based on the stability of the world in which past successful decisions tend to remain successful (stable predictions), while others rely on foreseeable dynamic changes in the environment (dynamic predictions). How does the brain learn to make these distinct predictions? I propose to address this question by combining cutting-edge behavioural, neurobiological and computational tools in mice. I will investigate whether the neurotransmitter dopamine, a central component of the brain’s learning circuits, plays a role in this learning process. Specifically, I hypothesize that dopamine regulates distinct prediction strategies through the modulation of neural circuits in two brain areas: the striatum and prefrontal cortex. I will first identify the behavioural signatures of stable and dynamic prediction strategies by training mice to perform visual decisions in environments affording both types of predictions, and will develop computational models of decision-making that capture mouse behaviour. I will then investigate the roles of dopamine in this learning by measuring the release of dopamine in prefrontal cortex and striatum using novel imaging techniques. Finally, I will determine the causal role of dopamine by manipulating dopamine signals in the two brain areas, using optogenetic tools. This research will provide fundamental insights into the neural bases of decision-making, and could shed light on clinical conditions that compromise decision-making and cognition.
2022
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Grant Awardees - Early Career
Biofilm heterogeneity as an evolutionary mechanism for resilience to complex environments
FUSCO Diana (ITALY)
Physics - University of Cambridge - Cambridge - UK
TROPINI Carolina (CANADA)
Dept. of Microbiology and Immunology and School of Biomedical Egineering - University of British Columbia - Vancouver - CANADA
RUIZ PESTANA Luis (SPAIN)
Civil, Architectural, and Environmental Engineering - University of Miami - Coral Gables - USA
Biofilms are structured communities of bacteria that grow at interfaces and have a remarkable ability to adapt and thrive in a tremendous diversity of hostile environments, including antibiotic-impregnated prosthetic implants. As such, biofilms are the most pervasive life-form on Earth. Our understanding of how biofilms achieve and have evolved this amazing resilience is woefully incomplete, as evidenced by our inability to disrupt detrimental biofilm formation. We hypothesize that phenotypic plasticity and biofilm morphology are coupled and have coevolved to promote optimal adaptation and survival in fluctuating hostile environments. We formulate this hypothesis based on 1) the correlation between biofilm morphology and phenotypic spatial organization 2) the widespread phenotypic heterogeneity among bacterial species, and 3) the multiple mechanisms through which functional and phenotypic diversity may confer advantages to biofilms. While isolated parts of this problem have been investigated, the intrinsic coupling between the mechanics, microbiology and evolution across multiple scales has not yet been explored. Our overall goal is to understand the feedback between cell-to-cell phenotypic heterogeneity, local physico-chemical conditions, and macroscale biofilm morphology, and to elucidate its evolutionary path and role on the amazing resilience of biofilms. Our research plan consists of three aims. First, we will learn the microscopic rules that govern the interplay between mechanical forces and gene expression. Second, we will determine whether and how phenotypic plasticity and associated biofilm morphology in the wildtype confers a fitness advantage to the biofilms. Third and last, we will elucidate how phenotypic heterogeneity could have spontaneously evolved. Our approach consists of a synergistic combination of a bottom-up multiscale modeling framework to map the mechanisms that control the feedback and co-evolution between phenotypic heterogeneity and biofilm morphology, in-vitro microfluidics and top-agar setups to inform and validate the computational models, directed evolution experiments, and in-vivo characterization of gut microbial biofilms to corroborate and revise our in silico understanding of biofilm behavior. The completion of this work will enable an integrated model of the role of heterogeneity in establishing biofilm resilience.
2022
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Long-Term Fellowships - LTF
Microtechnology-based limbic-cortex axis in 3D: modeling human neurodevelopment and disease
GARONE Maria giovanna (.)
. - Murdoch Childrens Research Institute - Parkville - AUSTRALIA
VELASCO Silvia (Host supervisor)
Stem cell-derived 3D organoid models hold great promise for studying processes of human brain development that would not otherwise be experimentally accessible. The amygdala is the component of the limbic system that regulates emotion and behavior, making extensive connections with the cerebral cortex and hippocampus. Its alterations have recently been highlighted as hallmarks of neurodevelopmental diseases, such as autism spectrum disorder (ASD). Despite recent advances in the generation and characterization of 3D systems replicating brain regions in vitro, models of the amygdala are still missing. Therefore, I propose to develop an innovative method to differentiate human induced pluripotent stem cells (iPSC) into amygdala-like brain organoids (hAmyOs). By using microtechnology-based methods to improve nutrient delivery and exchange, I aim to establish a next-generation 3D system to recapitulate the mutual interactions among the human cortex, amygdala, and hippocampus. By taking advantage of this novel 3D hiPSC-derived cortex-amygdala-hippocampus assembloid system, I will explore aspects of neuronal biology and function involved in human brain development and disease. I will focus on ASD mutant 3D systems to investigate defects of connectivity among defined brain regions with long-term live imaging and functional assays. Moreover, I will leverage single-cell-omics technologies to unbiasedly discover cell-type specific abnormalities and pathogenic mechanisms associated with mutation of ASD genes. Our research will provide a platform to study limbic-cortex connections involved in human development and for modeling circuit organizations and neurodevelopmental diseases.
2022
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Long-Term Fellowships - LTF
Metabolic and cell–cell interactions of Helicobacter pylori and stem cells of the gastric glands
GEIER Benedikt (.)
. - Stanford University School of Medicine - Stanford - United States
AMIEVA Manuel (Host supervisor)
Virulent strains of the global pathogen Helicobacter pylori (Hp) significantly increase the risk of developing gastric cancer. Recently, Hp has been described to form clonal microcolonies directly on the epithelial surface deep within the gastric glands, where they affect the proliferation and gene expression of epithelial stem cells.
My aim is to reveal the molecular details of how these gland-associated Hp strains shape this niche and how virulent strains promote gastric cancer.
To study metabolic interactions in situ I have developed an approach combining fluorescence labeling and high-resolution mass spectrometry imaging. I will to translate my approach for analyzing how different Hp strains and epithelial stem cells change their metabolome during colonization of the gastric gland microniche. To reveal the metabolic heterogeneity of Hp microcolonies that grow on the epithelia and to understand the underlying cell-cell interactions, I propose to integrate metabolite imaging with 3D correlative light and electron microscopy. Two experimentally tractable infection models developed by the host lab will serve me as study systems: a chronic Hp infection model of murine stomachs, and a human organoid model that mimics different regions of the gastric gland epithelium. I will infect both systems with genetically modifiable, isogenic Hp strains to show how virulence factors modulate the site-specific metabolism and ultrastructure of epithelial stem cells.
Here, I plan to develop a framework to investigate fundamental interactions between microbial strains and human epithelia to shed light on how Hp promotes gastric cancer by colonizing the microniche of the gastric glands.
2022
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Long-Term Fellowships - LTF
Uncovering the nuclear dynamics of telomeres upon replication stress
GONZALEZ MANJON Anna (.)
. - The University of Sydney - Sydney - AUSTRALIA
CESARE Tony (Host supervisor)
Regulated spatiotemporal nuclear organization is critical for genome function. During my PhD I demonstrated that disrupted chromatin organization at the nuclear lamina can mediate chemotherapy resistance through altered gene expression. As a post-doc, I will explore how dynamic alteration of nuclear spatiotemporal organization promotes genome stability during the replication stress response (RSR). The Cesare lab identified that nuclear actin forces potentiate movement of replication-stressed chromatin, including telomeres, towards the nuclear periphery to facilitate homology directed repair. Telomeres are an exceptional model for this study because straightforward methods exist to induce telomere-specific replication stress and determine telomere interatomic networks. Telomeres are also suitable to live imaging and interact with nuclear domains/condensates during replication stress through unknown mechanisms. Using this telomere model, I will examine the following aims that explore open questions on nuclear dynamics. i) Identify the regulators of RSR-dependent telomere movement using time resolved APEX2 interatomics profiled by mass spectrometry. ii) Characterize how telomere dynamics during replication stress alters both local and global chromatin organization through ChIP, Hi-C/4C, and ATAC-seq methods. iii) Study the consequences of perturbed telomere localization following experimentally directed telomere movement to nuclear domains/condensates. Each aim will include functional interrogation of the revealed pathway/consequences. This study will enhance our understanding of RSR-dependent chromatin dynamics and revel the impact of these processes on genome stability.
2022
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Grant Awardees - Program
Intracellular voltage control of directional cell migration
SAEZ Pablo (CHILE)
Department of Biochemistry and Molecular Cell Biology (IBMZ) / Cell Communication and Migration lab - University Medical Center Hamburg- Eppendorf | UKE - Hamburg - GERMANY
KRISHNAN Yamuna (INDIA)
Department of Chemistry - Gordon Centre for Integrative Science - Chicago - USA
GOV Nir (ISRAEL)
Department of Chemical and Biological Physics - Weizmann Institute of Science - Rehovot - ISRAEL
Cell migration is pivotal to wound healing, the immune response, and cancer. When a cell moves within a tissue it experiences a complex landscape, facing barriers as well as other cells in set topologies. When cells are moving towards a designated target - referred to as directional migration - they are attracted by specific chemical cues. These cues compel cells to adopt a preferred path along which they often face obstacles that generate bifurcating arms, of which one emerges as the winning direction. One way that cells sense barriers is by activating ion channels on their surface, which changes the membrane potential (MP) across the cell membrane. Due to the lack of tools it was so far impossible to expose the links between MP and directional migration. Ion channels on organelles can also contribute to changes in MP. Migrating cells use polarity as a navigation system, which in turn, is reflected in the organization of organelles - raising exciting questions. How do single cells choose a direction of migration? Do changes in MP at the cell surface and in organelles regulate this decision? Is there a cell-surface-to-organelle axis of communication that drives this decision? We propose to study how cells choose a direction between competing arms formed during movement. We posit that when a moving cell faces a bifurcation, ion channel activity at the plasma membrane changes MP, modifies the local actin flow, thereby contributing to the process of favoring an arm that sets the direction (similar to the front wheel and handle of a bicycle), while organelles at the cell rear respond and contribute to the forward movement (analogous to the back wheel of a bicycle). To test this idea, we will use new technologies that measure MP on the cell surface and in organelles of cells while they are migrating and choosing a direction. The data obtained will be integrated into a theoretical model, which we expect will describe and predict the direction of migration. Indeed, the ability to predict cell migration is an essential precursor to controlling its movement. Controlling cell movement can lead to accelerated wound healing, prevention of metastasis or sculpting of the immune response.
2022
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Grant Awardees - Program
Trichomes: uncovering principles of forming complex 3-dimensional shapes by cellular morphogenesis
GROSSNIKLAUS Ueli (SWITZERLAND)
Institute of Plant and Microbial Biology - University of Zurich - ZURICH - SWITZERLAND
KONDO Shigeru (JAPAN)
Frontier Bioscience - Osaka University - Suita - JAPAN
While experimental and theoretical studies have provided a deep understanding of the three-dimensional formation of tissues and organs, it largely remains a mystery how a single cell acquires its particular shape. One reason is that the complexity of cellular morphogenesis makes a mathematical description difficult because, in contrast to tissues, cells cannot be used as units in the mathematical model. Furthermore, the many processes that occur simultaneously in a single cell and influence each other, necessitate multi-component, interrelated models. Finally, locally restricted manipulations in specific regions of the cell are required to test certain aspects of the models for cellular morphogenesis. It is thus clear that solving such a complex problem depends on advances in both theory and experiment, requiring a research environment where theoreticians and experimentalists work closely together. We will tackle this problem through cooperation of the Grossniklaus and Kondo groups, specializing in plant developmental biology and mathematical modeling, respectively. The Grossniklaus group will use cell biological, biophysical, and photochemical approaches to investigate the individual processes of trichome morphogenesis. The Kondo group will perform simulations to understand how individual phenomena are integrated to produce the complex morphology of trichomes. Through this interdisciplinary collaboration, we will shed light onto the fundamental principles of cellular morphogenesis.
2022
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Long-Term Fellowships - LTF
Mapping the neuromodulatory heterogeneity in decision making
HAGIHARA Kenta m. (.)
. - Allen Institute for Brain Science - Seattle - United States
SVOBODA Karel (Host supervisor)
Small groups of neuromodulatory (NM) neurons send brain-wide projections and influence diverse brain functions. Failures of NMs are associated with debilitating neurological and psychiatric disorders. Although NM systems are often thought of as diffuse, there is a complex tapestry of heterogeneity within each system. An outstanding question is how NM systems exert specific effects on circuit subsystems during behavior.
Systematic interrogation of this question requires dissecting the diversity of NM cell types and their connectivity to identified target neurons and their NM receptors at multiple spatial scales. In my post-doctoral program, I will take a multi-faceted approach to examine the influence of serotonergic (5HT) neuron types on their postsynaptic targets and on neural ensemble dynamics in frontal cortex.
My research will first define sub-types of 5HT neurons in the dorsal raphe projecting to the frontal cortex by combined analysis of transcriptome and whole-brain anatomical reconstruction. I will gain genetic access to these types using enhancer adeno associated viruses. Next, using expansion microscopy and multiplexed immunostaining, I will examine synapse-resolution connectivity of 5HT neuron types by characterizing their post-synaptic receptor subtype distribution in target neurons. Finally, by simultaneously measuring activities of 5HT subtypes and their targets in mice engaged in foraging behavior, I will examine how such heterogeneous 5HT modulation influences population coding underlying economic decision-making. Our approach will provide a blueprint for mapping the NM heterogeneity in general and may reveal new targets for clinical intervention.
2022
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Cross Disciplinary Fellowships - CDF
Quantum microscopy of neuron electric signals
HANLON Liam (.)
. - École Normale Supérieure Paris-Saclay (ENS Cachan) - Gif-sur-Yvette - FRANCE
TREUSSART Francois (Host supervisor)
MOTHET Jean-Pierre (Host supervisor)
Electrophysiology is the gold standard to study neuron function at sub-µs resolution, but it lacks spatial resolution and is invasive. Various microscopies have been introduced to overcome these limitations and image a number of neuron signals simultaneously at high spatio-temporal resolutions. Voltage-sensitive dyes are one such technology but despite increasing temporal performance, it still lags behind electrophysiology techniques. Hence a sensor of neuronal electrical activity that would combine the high spatial resolution of optical microscopy and the fast time response of electrophysiology is still missing. Recently, quantum properties of atomic size systems have been harnessed in this field such as the Nitrogen-Vacancy (NV) defect in diamond. The NV has rapidly become a table-top equipment used to probe magnetic properties of novel materials at the nanoscale. Its translation to neuron sensing has been demonstrated [Barry2016], but limited to a giant axon with low spatial resolution. To improve such sensor performance I recently proposed a unique theoretical approach in which I harness NV ability to sense an electric field like in electrophysiology in diamond nano-pillars [Hanlon2020]. I now seek to implement neuron NV-electrometry in a laboratory possessing both NV physics and neuro-biology expertise. LuMIn lab at ENS Paris-Saclay will provide such cross-disciplinary expertise. I will conduct my work under the supervision of Prof. Treussart, with key inputs from Prof. Roch (NV magnetometry expert) and Dr Mothet, neurophysiologist. This expertise would allow me to design the NV neuro sensing experiment and test its efficacy against other sensing mechanisms.
2022
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Long-Term Fellowships - LTF
Understanding the neural mechanism underlying affiliative social behavior
HAYAT Hanna (.)
. - The Regents of the University of California, Los Angeles - Los Angeles - United States
HONG Weizhe (Host supervisor)
Social interactions between individuals are a hallmark of human society and involve two or more individuals engaging with one another. Whereas neural correlates of behaviors such aggression and mating have been studied extensively, little is known about the brain circuits that promote affiliative social interactions, which are crucial to maintain social cohesiveness and to the physical and emotional well-being of social species including humans. One of the most common affiliative behaviors observed across a large range of species is allogrooming, but the neural mechanisms underlying this behavior remain largely unknown. Here I propose to use high-density Neuropixels probe to record simultaneously hundreds of neurons from several brain regions during allogrooming (e.g. one probe can record activity from the medial amygdala, the hippocampus and thalamus simultaneously). Neuropixels enables recordings from local populations of neurons in one region as well as several populations across many regions, an essential step toward better understanding of global activity coordination during behavior. It will give me the opportunity to identify brain regions involved in social grooming, to decipher neuronal activity patterns involved in allogrooming from sensory input to motor output and to understand the inter-play and correlated activity between those regions. Using computational tools, I will build predictive models of behavior based on the brain activity. Investigation of the neural circuitry that controls affiliative social contact may help us understand the deficits of social behavior observed in neuropsychiatric conditions such as autism.