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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
2024
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Grant Awardees - Early Career
The Emergence of Collective Intelligence: Understanding Human Behavior through AI Agents
RUIZ-GARCIA Miguel (SPAIN)
- Universidad Complutense de Madrid - Madrid - SPAIN
SPITZER Markus (GERMANY)
- Martin Luther University Halle-Wittenberg - Halle - GERMANY
SAXE Andrew (United States)
- University College London - London - United Kingdom
TEICH Erin (United States)
- Wellesley College - Wellesley - United States
We aim to understand the fundamental principles that lead to the emergence of collective intelligence (CI) in groups of humans. We will work toward this understanding by modeling and perturbing the emergent dynamics of teams of humans as they interact and collaborate to accomplish tasks on an online gaming platform. Ours will be an interdisciplinary effort that utilizes our combined expertise in behavioral science, machine learning and artificial intelligence, neuroscience, and complex systems theory: We will model the behavior of individual participants using reinforcement learning (RL) agents informed by cognitive science, and we will quantify the interaction patterns of participant groups during gameplay using tools from network science and information theory. The incorporation into our RL agents of different artificial neural networks that each resemble cognitive functions of the individual human mind, coupled with a precise network characterization of group dynamics, will allow us to compare collaboration patterns of humans and RL agents and isolate underlying cognitive features that may be operative in both groups.
We will first create a set of experiments that validate that our online gaming platform can be used to study CI, and that RL agents can be used to model human behavior on this platform. We will establish which patterns of interaction among agents (both human and RL) and which individual cognitive features of RL agents are especially correlated with CI. We will then perturb group behavior through the manipulation of several factors we hypothesize have a significant impact on human CI. Specifically, we are interested in understanding how a continuous change of individuals impacts CI and if the creation of generations could optimize the learning process of the collective. We will also study how CI is modulated by predators and other threatening factors, the overall diversity of the group in terms of participant ability within the game, and participants’ anticipation of each other’s behavior. The intersecting nature of our expertise will allow us to perform both types of experiments (human & AI), compare emergent group behavior, and uncover the underlying cognitive processes present in the individuals. Our findings may also have implications for fields such as decision-making in organizations, swarm robotics, and social behavior in animals.
2024
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Long-Term Fellowships - LTF
Unraveling the cellular and molecular dynamics of adult neurogenic niches
SÁNCHEZ Juan (ARGENTINA)
Champalimaud Research - Champalimaud Foundation (Fundação D. Anna de Sommer Champalimaud e Dr. Carlos Montez Champalimaud) - Lisbon - PORTUGAL
RHINER Christa (Host supervisor)
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2024
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Long-Term Fellowships - LTF
Understanding the role of endometrial compartmentalization in menstruation
SANCHÍS CALLEJA Fátima (SPAIN)
Department of Stem Cell and Regenerative Biology - President & Fellows of Harvard College - Cambridge - United States
MCKINLEY Kara (Host supervisor)
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2024
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Cross Disciplinary Fellowships - CDF
Brain-Wide Mapping of Neurochemical Activity Using Liposomal Nanoparticle Reporters
SHARMA Vinay (INDIA)
Biological Engineering - Massachusetts Institute of Technology - MIT - Cambridge - United States
JASANOFF Alan P. (Host supervisor)
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2024
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Long-Term Fellowships - LTF
The neural basis of naturalistic memory
SILVA Marta (PORTUGAL)
Biomedical Engineering - The Trustees of Columbia University in the City of New York - New York - United States
JACOBS Joshua (Host supervisor)
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2024
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Long-Term Fellowships - LTF
A quantitative in vitro approach to virus infection
SOUDIER Paul (FRANCE)
School of Physics and Astronomy - Regents of the University of Minnesota - Twin Cities - Minneapolis - United States
NOIREAUX Vincent (Host supervisor)
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2024
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Long-Term Fellowships - LTF
Mapping the interactions between bacteria in the microbiome for targeted strain replacement
STOKAR-AVIHAIL Avigail (ISRAEL)
Genome Biology - European Molecular Biology Laboratory (EMBL-Heidelberg) - Heidelberg - GERMANY
TYPAS Athanasios (Host supervisor)
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2024
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Long-Term Fellowships - LTF
Understanding the host-microbe arms race through the TLR5-flagellin axis
TAN Yi Han (SINGAPORE)
Microbiome Science - Max Planck Institute for Biology Tübingen - Tübingen - GERMANY
LEY Ruth (Host supervisor)
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2024
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Long-Term Fellowships - LTF
Following dance vibrations on a swarm: the emergent mechanics of honey bee collectives
VIJAYAN Sajesh (INDIA)
Biology - The University of Western Ontario - London - CANADA
MHATRE Natasha (Host supervisor)
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2024
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Long-Term Fellowships - LTF
The biophysics of causality – sensing and control of network dynamics by single neurons
VOITOV Ivan (CANADA)
Zuckerman Institute - The Trustees of Columbia University in the City of New York - New York - United States
POLLEUX Franck (Host supervisor)
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2024
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Long-Term Fellowships - LTF
Does the striatum use cerebellar motor state predictions to guide rapid and complex movement?
WEGLAGE Moritz (GERMANY)
Department of Organismic and Evolutionary Biology - President & Fellows of Harvard College - Cambridge - United States
ÖLVECZKY Bence (Host supervisor)
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2024
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Long-Term Fellowships - LTF
Exploring novel riboswitches in plants: uncovering new regulatory mechanisms for plant metabolism
XU Jin (CHINA, PEOPLE'S REPUBLIC OF)
Cell and Developmental Biology - John Innes Centre, Norwich, UK - Norwich - United Kingdom
DING Yiliang (Host supervisor)
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2024
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Long-Term Fellowships - LTF
A nucleus-driven paradigm of mechanotransduction and morphogenesis
YOSHIDA Mari (JAPAN)
Genetics and Developmental Biology - Institut Curie - PARIS - FRANCE
BELLAÏCHE Yohanns (Host supervisor)
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2023
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Long-Term Fellowships - LTF
Deciphering the Role of Outer Radial Glia in Autism
AHMED Mai (EGYPT)
Yun Li Lab - The Hospital for Sick Children - Toronto - CANADA
LI Yun (Host supervisor)
Autism Spectrum Disorder (ASD) is a devastating neurodevelopmental disorder that causes deficits in social interaction and behavior. To date, 1031 genes are linked to ASD, suggesting its strong genetic background. However, how perturbations in these genes contribute to ASD pathology at the cellular and molecular levels remains largely elusive. Outer radial glia (oRG) are a recently identified population of neural stem cells that is highly enriched in the brains of humans and higher primates. oRG generate the majority of human cortical neurons and contribute to cortical expansion and folding. In this project, we hypothesize that oRG are involved in the pathology of ASD based on several observations. The brains of ASD patients during early development show altered growth and folding, which suggests possible defects in oRG proliferation or differentiation. In addition, a study published by the Li lab found that a mutation in a known ASD gene led to increased proliferation of oRG. Here, I aim to employ CRISPR-based knockout screens to investigate the role of oRG in ASD pathology using human pluripotent stem cell (hPSC)-derived oRG in 2D neural cultures and 3D brain organoids. To realize my aim, I will perform CRISPR screens in arrayed and pooled formats to determine which ASD gene knockouts perturb oRG at both the functional and transcriptomic levels. Based on the results of the screens, I will select high-potential ASD genes that induced significant changes in oRG. Then, I will generate 3D cortical organoids from stable CRISPR knockout hPSC lines and examine in detail how ASD gene disruption affects oRG dynamic behavior, oRG-derived neuronal populations, and organoid development. By leveraging human stem cell models, together with the recent advances in CRISPR screens and single-cell transcriptomics, the proposed study provides a targeted large-scale approach to fill a current gap in our knowledge on the role of oRG in ASD pathology. On a global scale, my study will shed light on the different gene networks that converge within oRG for ASD pathology, which is expected to pave the road for potential biomarkers and therapeutic targets that can improve disease outcomes in ASD patients.
2023
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Long-Term Fellowships - LTF
Profiling tumor proteolysis with genetically-encoded signaling integrators
ALGOV Itay (ISRAEL)
Cancer biology - Dana-Farber Cancer Institute - Boston - United States
ZHOU Xin (Host supervisor)
Elevated extracellular protease activity is a hallmark of cancer, known to play an important role in shedding and activating receptors and remodeling the extracellular matrix. Technologies that allow us to understand the complexity, dynamics, and heterogeneity of extracellular proteolysis would significantly advance our understanding of how proteases impact tumor growth and metastasis, and inform how we could harness elevated proteolysis to design safer cancer drugs.
It remains difficult to characterize tumor microenvironment protease activities with current molecular tools. RNAseq can determine intracellular transcript levels but doesn’t report protease activities or extracellular proteolysis. Protease sensors, such as genetically encoded reporters or small molecule probes, only allow testing of one substrate sequence at a time, which prevents us from a systematic understanding of the proteolysis landscape.
To break the technology barrier for a deeper understanding of the protease activities in the tumor microenvironment, I propose to develop proteolysis signaling integrators (PSIs) that can transform a proteolysis event into a transcriptional event within a defined time window. I have designed two systems for the PSIs. The first is based on leucine zippers, alpha-helical dimerization motifs found in transcription factors. The second one is based on Protease-Activated Receptors (PARs), G protein-coupled receptors activated by proteases. In both systems, I have designed to couple a proteolysis event of a substrate sequence to release a Gal4 transcription factor (TF). The design of PSIs is modular so that a large library of substrates can be encoded and tested simultaneously. A small-molecule controllable destabilizing domain (ddDomain) will be incorporated into a PSI to control the time of expression. Tumor cells engineered to express the library of PSIs will be implanted in mice and activated for expression after the tumor grows to a specific size. If a proteolysis event happens, the Gal4 TF will drive transcription of an enhanced green fluorescent protein (EGFP), resulting in a quantitative signal of the proteolytic events. Following isolation of the tumor, cells with low, medium, and high EGFP signals will be separated and sequenced to determine the propensity of proteolysis for different substrate sequences. The development of PSIs has the potential to transform how we characterize extracellular protease activities, and the gained knowledge will inform the development of a new generation of protease-based prodrugs.
2023
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Grant Awardees - Program
Bacterial targeting of the host epitranscriptome
HARTLAND Elizabeth (.)
Monash University - Clayton - AUSTRALIA
ALLAIN Frédéric (.)
Swiss Federal Institute of Technology in Zurich (ETH Zurich/ETH Zürich) - . - .
HELM Mark (.)
Johannes Gutenberg University of Mainz - . - .
The post-transcriptional processing and modification of cellular RNA provides an additional level of gene regulation that is known as the epitranscriptome. However, despite current knowledge of RNA modifications, the functional significance of many epitranscriptomic changes within the cell is unknown. Here we will explore the impact of bacterial infection on the host epitranscriptome using methods to identify the direct and specific modification of host RNA by bacterial pathogens. Many host-interacting bacteria use specialised protein secretion systems to inject “effector” proteins into eukaryotic cells that target various cellular processes to promote bacterial survival. Although many bacterial effector proteins are known to mediate post-translational modifications of host proteins, effectors that directly modify host RNA and alter the epitranscriptome have not been described. We hypothesise that host-interacting bacteria harbour undiscovered RNA-binding effector proteins that post-transcriptionally target eukaryotic RNA with novel modifications. Such RNA modifying effectors would offer the potential to investigate the significance of RNA modifications in host cell responses and functional biology.
The specific aims are to: 1. Discover bacterial effector proteins that bind eukaryotic host RNA during infection using Legionella species as model intracellular bacteria by performing RNA-interactome capture (RIC) from host cell RNA. Epitope tagged RNA-binding effector proteins will then be used for cross-linking RNA immunoprecipitation (CLIP) of host RNA to identify RNA modifications using liquid-chromatography and mass spectrometry (LC-MS). 2. Define the host RNA targets of bacterial effectors and explore the structural basis of effector mediated RNA modifications using epitranscriptomics. Large-scale expression and purification of bacterial RNA-binding effectors with identified consensus RNA-modification motifs will be used for structural analysis of RNA-protein complexes. 3. Investigate the impact of effector-mediated host RNA modifications on the cellular response to infection by assessing bacterial mutant strains for intracellular replication defects and changes in host transcriptional responses to infection. The biodynamics of RNA-binding effectors and their modified host RNAs will be explored in vitro using novel liquid-liquid phase separation (LLPS).
2023
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Long-Term Fellowships - LTF
Investigating the cell-matrix mechano-chemical feedback loops as determinants of tissue fate
ALLANKI Srinivas (INDIA)
Tumor Cell Biol. Lab - The Francis Crick Institute Ltd - London - United Kingdom
SAHAI Erik (Host supervisor)
Emergent tissue architecture is orchestrated by the mechano-chemical feedback interactions among the cellular and extracellular components, across scales. While the biochemical principles of tissue organization have been well studied, the mechanical and biophysical aspects remain less well understood. In a homeostatic tissue, the constituent cells both deposit and maintain the extracellular matrix (ECM), thereby determining tissue mechanics, and are responsive to the mechanical properties of the ECM. An imbalance in these processes can lead to pathologies such as fibrosis and cancer. Hence, remodeling the spatial and biochemical interactions of cells and the ECM can decide the tissue fate in between health and disease. Moreover, physiological aging is associated with changes in tissue structure and mechanics, which may relate to the development of pathologies. However, a holistic view on the in vivo principles governing tissue fate as a function of the complex feedback loops among cell types, cell states, ECM, and tissue mechanics is yet to be defined.
I hypothesize that mechanical heterogeneity within the homeostatic tissue leads to the formation of stiffness-dependent cell states, which prime the cells in stiff regions to disease. Hence, the aims are – 1) to characterize the in vivo spatial arrangement of various cell types and their respective transcriptional states as a function of the surrounding ECM and tissue mechanics, and 2) to identify specific cell-matrix feedback loops that define the tissue fate.
Using the homeostatic and fibrotic murine skin as models of health and disease, I will spatio-temporally map their mechano-chemical properties by combining mechanical mapping (nano-indentation) with high-resolution spatial matrisomics (imaging mass cytometry) and transcriptomics (Stereo-seq). With these data, I will uncover the spatio-temporal correlations among tissue mechanics, topology, and biochemical properties, including cellular composition, arrangement, and their transcriptomes, as well as the ECM alignment and stiffness. Next, to determine the causality of these correlations, I will manipulate the cell-matrix loops in silico using agent-based modelling and in vitro using co-cultures with stiff vs. soft matrix-generating fibroblasts. I will then systematically test these theories by using 4D live imaging coupled with nano-indentation in tissue explants. The shortlisted feedback loops will be manipulated in vivo in the homeostatic tissue using mosaic expression systems and gene-level perturbations (Perturb-seq) and assayed for the tissue fate. Finally, I will test whether these cell-matrix loops are conserved in human pathologies, including skin cancer/fibrosis.
Altogether, this project will provide a comprehensive understanding of disease emergence and how local mechano-chemical feedback loops orchestrate the macroscopic tissue fate in space and time, and opens new avenues for generating preventive therapeutics.
2023
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Grant Awardees - Early Career
Encoding motion in an interface: the shape-morphing armored skin of pufferfish
AMINI Shahrouz (.)
Max Planck Institute of Colloids and Interfaces (Max-Planck-Institut für Kolloid- und Grenzflächenforschung) - Potsdam - GERMANY
RAFSANJANI Ahmad (.)
University of Southern Denmark (Syddansk Universitet, SDU) - . - .
CAMP Ariel (.)
University of Liverpool - . - .
Spiny pufferfishes, e.g., porcupinefish, defend themselves by transforming from a streamlined torpedo to a large, prickly sphere. This dramatic yet reversible shape morphing is achieved by highly mineralized hard spines anchored to a very extensible soft skin that stretches up to 40% as the body inflates. The armored skin is activated by body inflation: as the skin stretches, the sharp spines rotate into an erect position, rigidly pointing outward as a visual warning and mechanical defense. Interfacing between hard and soft tissues is ubiquitous in nature like bone and tendon, but it is very unusual for such an interface to embrace extensive, lifelong distortions while maintaining the material integrity. Remarkably, the skin-spine interface of pufferfish does exactly this function, dramatically morphing both skin and spines with every inflation-deflation cycle and using this transformation as a defense mechanism. How do puffers assemble this unlikely combination of extensible and rigid materials into a repeatedly stretched interface—without tearing themselves apart? How does the drastic skin extension drive and guide spine rotation? How do properties of soft skin and hard spine reciprocally shape dynamic movements? In this project, we integrate our expertise in mechanics, biology, and robotics to provide unprecedented insights into the multi-scale architecture and complex function of the porcupinefish’s armored skin. We will systematically investigate the dynamics of the body expansion, skin stretching, and spine erection and adapt the deployed structural and architectural strategies to create bio-inspired functional interfaces. The micromechanical experiments will reveal the secret to the integrity and performance of the interface of materials with contrasting properties. The musculoskeletal measurements, both on live animals and fresh tissues, shed light on the kinematics and functional morphology of the armored skin of pufferfish. The soft robotics model presents a cyber-physical twin for pufferfish capable of reproducing reactive behaviors consistent with its morphing behavior to verify and generate biological hypotheses. Our collaborative project unravels how the interfacial morphology of pufferfish skin encodes complex shape-morphing functions transferable to adaptive architectures for biomedical, surveillance, and environmental monitoring application.
2023
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Grant Awardees - Early Career
Decoding the sulfation codes in the glycocalyx
MILLER Rebecca (.)
Københavns Universitet (University of Copenhagen, UCPH) - Copenhagen - DENMARK
ANGGARA Kelvin (.)
Max Planck Institute for Solid State Research (Max-Planck-Institut für Festkörperforschung) - . - .
Large polysaccharides are widely found in nature. Arguably one of the most complex and biologically diverse groups of polysaccharides are the glycosaminoglycans (GAGs) that despite a relatively simple disaccharide repeating backbone attain enormous structural variation through decoration by sulfate groups. While many important and diverse bioactivities assigned to GAGs are believed to be directed by distinct patterns of sulfation along the large GAG chains, direct structural identification of these motifs remains largely unexplored due to analytic barriers. Therefore, our aim is to marry emerging technology advances to make a quantum leap in glycosciences with atomic-level sequencing and structural determination of polysaccharides at the single-molecule level. We hypothesize that precise genetic engineering of glycosylation in cells (RLM’s team at UCPH) will enable us to produce sufficiently homogeneous GAG chains for direct sequencing analysis by single-molecule imaging using electrospray ion-beam deposition and scanning tunneling microscopy (KA’s team at MPI). We focus on GAGs that through complex sulfation patterns orchestrated by 30 distinct sulfotransferases produce recognition landing paths - sulfation codes - for a myriad of GAG-binding proteins that serve essential functions in all metazoans. We will produce these GAGs from the library of cells, and they will be structurally characterized by imaging them one-molecule-at-a-time using scanning tunnelling microscopy to provide the visual form and shape. The images corroborated by ab initio calculations at the level of Density Functional Theory (DFT) will reveal structural GAG motifs that give rise to distinct bioactivities. We believe this interdisciplinary strategy will enable us to dissect the bioactive cues embedded in the long GAG chains. Moreover, we believe that the strategy of combining genetic glycoengineering to reduce the complexity and heterogeneity of GAGs combined with single-molecule imaging will lead to a major breakthrough in glycosciences, which will more generally open up opportunities for direct analysis of other types of polysaccharides, including bacterial lipopolysaccharides, plant polysaccharides such as chitosan, as well as more complex glycoconjugates such as proteoglycans and glycoproteins.
2023
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Grant Awardees - Program
Understanding fundamental mechanisms governing insect cell membrane deformability
GEROLD Gisa (.)
University of Veterinary Medicine Hannover (TiHo) - Hannover - GERMANY
ARIOTTI Nicholas (.)
Institute for Molecular Bioscience - . - .
PERRIMON Norbert (.)
President and Fellows of Harvard College, Harvard Medical School - . - .
Insect cell membranes differ from mammalian membranes by deformability, lipid content, lipid distribution in microdomains and membrane leaflet asymmetry. Enveloped insect-borne viruses require intimate interactions with cellular membranes to enter cells, replicate their genomes in cells and bud from cells. Despite fundamental biophysical differences between insect and mammalian membranes, insect-borne viruses can productively infect cells from both phyla. Decades of studies on insect-borne viruses have not addressed the machinery of insect membrane deformation and its exploitation by viruses.
Here we hypothesize that insect-borne viruses have evolved to biophysically manipulate membranes from both phyla and/or hijack physiological membrane properties from both phyla. Whether genes involved in membrane dynamics or deformation are genetically similar in insects and mammals or whether insects and mammals achieve similar outcomes using distinct sets of genes remains elusive to date. Therefore, our objectives are to bundle the knowledge from three disciplines to unravel fundamental membrane processes in insect cells and compare these to mammalian cells.
Working at the interface of insect genetics, membrane biophysics and virology our newly formed team has assembled innovative technologies to break through this barrier in the field. Through the combined expertise of the PIs, we will: 1. Employ gene editing libraries in insect cells to identify host factors steering virus – membrane interactions; 2. Visualize membrane deformation at high-resolution upon genetic manipulation in uninfected and virus-infected insect cells using time-lapse imaging, high resolution imaging and biophysical probes; 3. Assess the impact of membrane deformation on permissiveness to insect-borne viruses by infection assays and sophisticated virological assays probing virus entry, genome replication at plasma membrane microdomains and virus budding from insect cells. 4. Compare the membrane deformation mechanisms in insect cells to those in mammalian cells.
These studies will provide insight into mechanisms driving insect versus mammalian membrane shape and function. Thereby, they will revolutionize our understanding of virus adaptation across fundamentally different species.