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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
2020
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Long-Term Fellowships - LTF
Investigating the CNS lymphatic system and immune cell trafficking in brain metastasis
JORDAO Marta Joana Costa (PORTUGAL)
Department of Oncology - University of Lausanne / Ludwig Institute for Cancer Research - Lausanne - SWITZERLAND
JOYCE Johanna (Host supervisor)
Brain metastases (BrM) represent the most common and aggressive neurological complication of systemic cancers, typically arising from melanoma, lung and breast cancers. With most patients living just over one year following BrM diagnosis, it is essential to understand the multistage process of dissemination of cancer cells from the primary tumor to the CNS and the importance of the tumor microenvironment (TME) in which BrM develop, to uncover novel therapeutic targets. The brain TME comprises a diverse spectrum of resident and peripheral immune cells, glial, vascular, and cancer cells. As the CNS was previously believed to be devoid of a lymphatic system, the trafficking of these cells into the CNS was thought to occur only via blood vessels. However, we hypothesize that the recently identified CNS lymphatic system may represent a potential route for both cancer and immune cells to reach the CNS through the lymphatic vessels within the dura mater. For this reason, I aim to evaluate how the lymphatic network evolves during BrM establishment, to determine to what extent cancer cells and peripheral immune cells are being transported through the lymphatics into the CNS, and to identify which molecular cues are responsible for the recruitment of these cells to the dura mater. To address these goals, transcriptomic and histological analyses of the dural microenvironment, in vivo imaging of the dura mater, and manipulation of the lymphatic system will be performed at different stages of BrM development. This experimental strategy will allow me to determine the potential impact of the lymphatic system in BrM establishment, an intriguing link that has not yet been explored.
2020
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Cross Disciplinary Fellowships - CDF
Investigating mechanotransduction at a single molecule level
KASHCHUK Anatolii (UKRAINE)
Department of Physics and Astronomy - University of Florence - Florence - ITALY
CAPITANIO Marco (Host supervisor)
Cells respond to physical force-induced signals by converting the mechanical stimulus into a biochemical response. This process, termed mechanotransduction, is an integral part of cellular physiology and has a profound impact on many biological processes including cell development and differentiation. The project goal is to provide a better understanding of the molecular mechanisms of the initiating 'mechanosensing' and its connection to variations in gene expression by studying the dynamic features of this mechanism at a single molecule level. Force transmission is a highly dynamic process and its investigation requires single molecule techniques with high temporal resolution. Therefore, the immediate aim will be to take advantage of and improve a unique ultra-fast optical trap, recently developed by the supervisor's group at the University of Florence that will allow the investigation of protein-protein interactions in vitro. In particular, the researcher will study the interactions between actin and putative mechanosensitive proteins, under various conditions of mechanical load. In a parallel research line, the researcher will develop an experimental setup and a methodology to apply mechanical stimuli on living cells and monitor the changes in gene expression profiles, with sensitivity down to the single molecule. The aim will be to correlate external mechanical stimuli on specific membrane receptors to intracellular signaling pathways and gene expression profiles, thus creating a powerful tool to enhance our current understanding of the molecular mechanisms of mechanotransduction in vivo.
2020
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Grant Awardees - Program
Does Evolution Repeat Itself? Genome Evolution and Phenotypic Convergence in Island Lizards
LOSOS Jonathan (USA)
Dept. of Biology - Washington University - Saint Louis - USA
MENKE Douglas (USA)
Dept. of Genetics - University of Georgia - Athens - USA
KAWATA Masakado (JAPAN)
Graduate School of Life Sciences - Tohoku University - Sendai - JAPAN
WHITING Martin (USA)
Dept. of Biological Sciences - Macquarie University - Sydney - AUSTRALIA
One of the great questions concerns fate vs. chance. Are events destined to occur, or are they the result of specific antecedent conditions, any of which, were they different, would have led to a different outcome? Anolis lizards are recognized as among the best groups to investigate this question, and detailed study of their evolution has suggested a strong role for determinism. These studies, however, have focused on the phenotype; the extent to which genome evolution is deterministic or historically contingent is an open question. Until recently, detailed investigation of genome evolution has been limited to model organisms, for which little data are available on their ecology and behavior in natural settings, precluding study of the factors that have shaped their evolution. Now, advances in genomics and gene editing methods allow evolution to be studied in non-model organisms, permitting holistic studies from the genome to selective pressures in nature. Anolis lizards are the ideal group to combine genomic and organismal studies at multiple levels to address the extent to which evolutionary diversification is deterministic or contingent.
This project will proceed as follows:
Genomics: We will test for evolutionary determinism by investigating whether convergently evolved phenotypes are the result of the same or different genetic changes.
Functional Tests of Candidate Loci: We will take advantage of recent advances in gene editing to directly test the role of these genetic changes in producing convergent phenotypes. To do so, we will use CRISPR-cas9 gene editing to modify genes in the lizard Anolis sagrei. We will examine genetically modified offspring to test the hypothesis that sequence variants produce the putative phenotypes.
Behavior and Physiology: We will identify genes and the underlying sequence changes associated with the evolution of these traits, introduce these specific sequence variants into brown anoles, and then test whether the introduced sequence alterations produce the hypothesized behavioral and physiological phenotypes.
Natural Selection: Once we have identified genetic changes underlying putatively adaptive phenotypes, we will design field experiments to test the hypothesis that natural selection favors those genotypes/phenotypes under particular environmental circumstances.
2020
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Long-Term Fellowships - LTF
Investigating the effects of sleep on neural computations in the olfactory system
KIRSZENBLAT Leonie (AUSTRALIA)
Laboratory for Circuit Mechanisms of Sensory Perception - Riken Center for Brain Science - Wako - JAPAN
KAZAMA Hokto (Host supervisor)
Sleep is a reversible state of quiescence during which an animal loses awareness of the external world. Although sleep is important for many brain functions, the mechanisms that underpin sleep and its functions are still poorly understood. The fruit fly, Drosophila melanogaster, has become a popular model for sleep research, because of the ability to probe the molecules and circuits involved in sleep. In this study, we will investigate the neural mechanisms by which the brain suppresses perception during sleep, with a focus on the well-characterized Drosophila olfactory system. Firstly, we will establish a system in which we can image neural activity of olfactory circuits during sleep. Secondly, we will investigate how sleep alters odor representations. Thirdly, we will examine the neural mechanisms underlying this sleep-dependent olfactory processing. Finally, we will examine the functional impact of sleep on olfactory behaviour. Overall, this study aims to reveal fundamental principles of sleep functions in sensory perception.
2020
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Long-Term Fellowships - LTF
Role of post-translational modifications of mSWI/SNF chromatin remodeling complexes in human disease
KOREN-HAUER Shany (GERMANY)
Department of Chemistry - Princeton University - Princeton - USA
MUIR Tom (Host supervisor)
Precise control of gene expression is required for virtually all cellular functions, ensuring correct maintenance of cell identity and genomic stability. Chromatin remodeling complexes regulate gene expression and reorganize chromatin architecture by sliding, ejecting or changing the composition of nucleosomes along DNA. The ATP-dependent multi-subunit BRG-/BRM-associated factor (BAF or mammalian SWI/SNF) remodeling complex is one of the most frequently disrupted macromolecular assemblies in human cancers, as well as in a range of autism and intellectual disability syndromes. While the molecular activities of BAF complexes and their role in driving disease mechanisms are intensively studied, the specific roles for post-translational modifications (PTMs) on individual BAF subunits in mediating overall BAF complex function has remained largely unexplored. Further, specific upstream signaling pathways that alter BAF remodeling activity via placement of subunit PTMs in both healthy and disease states have not been explored. To address these key questions, we aim to define the compendium of BAF subunit PTMs, assess their functional roles, and identify the corresponding PTM-mediating enzymes and pathways. These approaches will enable us to answer fundamental questions regarding whether and how BAF subunit PTMs control complex activity, targeting, and functions in mediating DNA accessibility lending new insights in to remodeler function in both healthy and disease states. Delineating the pathways which activate or repress BAF function may implicate novel strategies for therapeutic intervention in cancer and other diseases.
2020
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Long-Term Fellowships - LTF
Role of cholesterol metabolism in aging model of neuronal recovery
KUK Alvin Chun Yin (AUSTRALIA)
Cardiovascular and Metabolic Disorders Programme - Duke - NUS Medical School - Singapore - SINGAPORE
SILVER David (Host supervisor)
Advancing age is a major risk factor for many neurodegenerative diseases, but the underlying mechanisms are not understood. The Crowston laboratory has recently demonstrated age-related impairment of neuronal recovery and associated increased neuronal death in an established optic nerve injury model. The predominant age-related changes were localized to excitatory synapses that activate ganglion cells in the retina. Because cholesterol is known to be important for synaptogenesis and recent evidence linking mutations in cholesterol metabolism with numerous neurodegenerative diseases, we hypothesize that age-related changes in cholesterol metabolism could be responsible for the observed defect in neuronal recovery through loss of synaptic plasticity. To test this hypothesis, experiments would be divided into two stages, a discovery stage and a hypothesis-driven stage. The aim of the discovery stage is to compare central nervous system (CNS) cholesterol metabolism in young versus aged animals, either with or without injury. If the hypothesis is correct, aged animals would be expected to have altered CNS cholesterol metabolism more susceptible to injury challenge. The hypothesis-driven stage is to then test how manipulating CNS cholesterol metabolism impacts synaptogenesis and recovery of visual function. This project will be done in collaboration with the Silver lab which has expertise in lipid transport and metabolism. Results would further our understanding of cholesterol metabolism in the aging CNS and how it impacts neuronal recovery.
2020
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Long-Term Fellowships - LTF
Structural and biochemical investigation of Xist-mediated X-chromosome inactivation
KUMAR Ananthanarayanan (INDIA)
Department of Molecular, Cellular and Developmental Biology - Yale University - New Haven - USA
PYLE Anna Marie (Host supervisor)
The majority of the human transcriptome encodes non-coding RNAs that are not translated into protein. Long ncRNAs (LncRNAs) are 200 nucleotides or longer, and are involved in many cellular processes, including embryogenesis and DNA damage repair. Xist is an evolutionarily conserved LncRNA that plays a key role in dosage compensation in eutherian females. It does so by recruiting protein complexes that deposit repressive marks on histones on one X chromosome (XC), thereby leading to heterochromatin formation. Recent computational and biophysical studies suggest that Xist, as well as other LncRNAs, adopt higher order tertiary structures similar to ribozymes and group-II introns. Nonetheless, no high-resolution 3-D structures of Xist and its associated protein complexes have been determined. Thus, the precise molecular mechanism of XC inactivation remains unclear. In this proposal, I aim to biochemically identify and reconstitute Xist ribonucleoprotein (RNP) complexes involved in spreading and silencing of the XC. I will then determine the 3-D structures of Xist-protein complexes using a combination of electron cryomicroscopy and X-ray crystallography. In combination with biochemical and biophysical assays, I will characterize the native proteome associated with Xist, as well as the contributions of Xist tertiary structure towards recruitment of protein machineries including the polycomb complexes. These studies aim to elucidate molecular mechanisms of how Xist carries out gene silencing of the XC.
2020
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Grant Awardees - Program
Stable propagation of a minimal synthetic cell
KURUMA Yutetsu (KOREA, REPUBLIC OF (SOUTH KOREA))
X-star - Japan Agency for Marine-Earth Science and Technology - Kanagawa - JAPAN
WANG Anna (AUSTRALIA)
School of Chemistry - University of New South Wales, Sydney - UNSW Sydney - AUSTRALIA
ROGERS W. Benjamin (USA)
Martin A Fisher School of Physics - Brandeis University - Waltham - USA
All existing life on Earth is the result of natural selection acting upon earlier forms of life, shaping the lineages over time. In order for selective advantages to accumulate over successive generations, the offspring must retain some attributes of the parent. Thus at some point early in life’s origins, a sustainably propagating cell must have emerged, one that could divide and produce offspring with reasonable fidelity. While genetic information propagation is largely understood--nucleic acids or their precursors preserve information by sequence complementarity--it is less obvious how the other properties of primitive cells, such as their membrane composition, could have been preserved across many generations. This remains a key open question in the emergence of life on Earth.
We propose to answer this question by taking a bottom-up approach, in which we attempt to build a synthetic cell that can accomplish the essential tasks of stable propagation--membrane growth, feeding, and division--using the simplest components possible. In order to succeed, we will address a number of questions fundamental to biology. For example, to create a synthetic cell that can grow its own membrane, we must discover the mechanisms governing phospholipid synthesis, which could be determined by the rates of molecular motion or chemical reactions, the availability of nutrients, or incompatibilities between the molecules involved. Similarly, to feed our synthetic cell to sustain its growth, we must elucidate the physical rules governing membrane permeability. Finally, to induce division, we must understand the fundamental physics governing membrane bending, curvature, and fusion.
We will combine cutting-edge techniques and perspectives from across all three fields of science to succeed in this ambitious endeavor. Kuruma, a biologist, will synthesize membrane material from simple building blocks in vesicles. Wang, a chemist, will analyze the properties of membranes to understand lipid packing, linking together membrane permeability with membrane fusion. And, Rogers, a physicist, will explore the physics of membrane bending and devise new strategies to induce cell fission. By working together, we will paint a comprehensive picture of how stable cell propagation could have emerged, as well as solve one part of the puzzle of how life as we know it could have come to exist.
2020
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Grant Awardees - Program
Cell death, fluctuating asymmetry, and the precise specification of Drosophila organ sizes
LUBENSKY David K. (USA)
Dept. of Physics - University of Michigan - Ann Arbor - USA
LEOPOLD Pierre (FRANCE)
Genetics and Developmental Biology Unit - Institut Curie – Centre de Recherche - Paris - FRANCE
How organs control their growth to achieve the correct final size is an enduring mystery of biology. In wildtype Drosophila, for example, left and right wing areas rarely differ by more than 1%. We previously found that the hormone Dilp8 controls this developmental precision, as in absence of the hormone, the fluctuating asymmetry (FA) of bilateral organs is strongly increased. In this proposal, we hypothesize that the hormone Dilp8 and cell death cooperate to limit wing size variability. To test this idea and explore its consequences, we will integrate methods from developmental biology with quantitative data analysis and modeling from physics. In particular, we will show how changes in cell death in dilp8 mutants are quantitatively related to changes in final wing size. Our results will provide new insights into how organ size is controlled and refined in biological systems.
2020
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Long-Term Fellowships - LTF
Deciphering the functions and mechanisms of brain-wide motor representations
LEV Itamar (ISRAEL)
Department for Neurobiology - University of Vienna - Vienna - AUSTRIA
ZIMMER Manuel (Host supervisor)
Brain-wide representations of ongoing behavior were recently observed in neuronal activity patterns measured form various organisms such as worms, flies, and mice. Surprisingly, also primary sensory areas, like the V1 visual cortex in mice, previously thought to exclusively represent sensory information are also strongly modulated by behavioral variables like running speed. While this phenomenon seems to be prevalent, its functions and underlying neuronal mechanisms are elusive. I hypothesize that motor commands are integral components of sensorimotor transformations. Like others have suggested for the V1 area, I propose that this sensorimotor integration allows behavior-dependent sensory gain control, and more speculatively also involves predictive coding, i.e. that perception is tuned to unexpected outcomes of the animal's explorative movements. To address these hypotheses, I will use the tractable model organism C. elegans which is amendable to the cutting-edge whole-brain calcium imaging technology. I will develop new whole-brain imaging assays in freely-moving worms. I will then use these assays to search for gain-control circuits where the sensitivity of sensory neurons is modulated by different behavioral states. I will also look for predictive-coding circuits involving error-coding neurons, sensitive to unexpected stimuli. To study the behavioral relevance of these mechanisms, e.g. during navigation, I will interfere with the neuronal activity of the relevant circuits via optogenetics and other transgenic inhibition tools. Therefore, by combining these different approaches I aim to uncover generalizable functions and mechanisms of brain-wide motor representations.
2020
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Long-Term Fellowships - LTF
The ontogeny of behavior
LEVY Dana Rubi (ISRAEL)
Department of Neurobiology - Harvard Medical School - Boston - USA
DATTA Sandeep Robert (Host supervisor)
Naturalistic behaviors are refined and stabilized throughout an animal’s life. Their formation is dependent upon multiple internal and external cues, giving rise to both stereotypical intraspecific responses and individually-unique behavioral patterns. The striatum has been widely implicated in controlling voluntary action and encoding behavioral modules and sequences in adulthood. However, how striatal dynamics might support and structure the evolution of behavior throughout development remains surprisingly unexplored. Here, I propose to incorporate longitudinal, unsupervised behavioral phenotyping with high-throughput in-vivo neuronal recordings in freely-behaving mice in order to characterize the evolution of naturalistic behavioral modules and their neural correlates from weaning to adulthood. To explore the interplay between external cues, circuit dynamics and behavioral plasticity, I will confound environmental features during development and study how behavioral adaptation is reflected in the underlying single-cell and population striatal codes. Finally, I will utilize this large-scale dataset to investigate the emergence of behavioral variation and to identify the neural correlates of individuality.
2020
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Cross Disciplinary Fellowships - CDF
Elucidating the acute cellular sensing and response pathways to severe hypoxia
LI Li (CHINA, PEOPLE'S REPUBLIC OF)
Department of Pharmaceutical Chemistry - University of California - San Francisco - USA
ALTSCHULER Steven (Host supervisor)
Hypoxia plays a central role in the pathogenesis of myocardial infarctions by causing immediate cellular damage within the short time scale of minutes to hours. Pathways that govern the acute response of heart tissue to hypoxia are poorly characterized. Currently, the procedure for stopping imminent tissue damage due to heart attack is percutaneous coronary intervention. Thus, systematically elucidating pathways involved in acute hypoxic response will lead to novel pharmacologic interventions aimed at protecting against the adverse cellular effects of hypoxia. One major challenge for the systematic study is that hypoxia response involves diverse processes, affecting cellular changes to metabolic, epigenetic, and transcriptional states, and hypoxia response is dynamic and can affect spatial organization within the cell. An appealing approach to overcome this challenge is phenotypic profiling, which offers a scalable, microscopy-based approach to convert complex cellular response to perturbations into high-dimensional vectors, referred to as phenotypic “profiles”. Here, I propose to apply phenotypic profiling to conduct a systematic study of the sensing and regulatory network governing acute cellular response to severe hypoxia in cardiomyocyte cells. My specific aims are to: (1) Establish a scalable platform for phenotypically profiling acute cellular response to severe hypoxia; and (2) Identify novel hypoxia sensors and regulatory pathways that govern acute cellular response to hypoxia using this platform.
2020
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Long-Term Fellowships - LTF
Recording and programming human retina cell fates
LIN Hsiu-Chuan (CHINA, REPUBLIC OF (TAIWAN))
Human Retina and Organoid Development Group - Institute of Molecular and Clinical Ophthalmology Basel - Basel - SWITZERLAND
CAMP Gray (Host supervisor)
It is a longstanding goal to decipher cell fate decisions during human development. Stem cell-based culture systems, combined with single-cell sequencing and CRISPR-Cas technologies, offer exciting possibilities to track human cell identities at unprecedented resolution and to engineer specific cell types with high precision. In this proposal, I will develop novel methods to record cell histories, trace lineages, and program human cell fates, with a focus on the human retina. In the first aim, I will develop a fate recording system in induced pluripotent stem cells (iPSCs) that unites evolvable barcodes with molecular memory recorders (Cas1/2) that capture expressed RNA into DNA. This will be used to simultaneously record real transcriptome and lineage histories along the path of cell fate acquisition. In the second aim, I will adopt the CRISPR-Cas12a(Cpf1) system that enables multiplexed gene activation to engineer cell fates based on predictions learned from single-cell transcriptome dissection of organ development. I will focus my project on human retina development where we have a well-characterized three-dimensional organoid culture system, and extensive data analyzing cell fates that emerge in these organoids. This focus will provide insights into the molecular mechanisms controlling human retinogenesis, and at the same time identify methods to engineer specific retinal cell types for therapeutic screening. The strategies and technologies developed in this project are applicable beyond the retina and will contribute to our understanding of general cell fate decisions in humans and guide cell type engineering with clinical potential.
2020
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Grant Awardees - Early Career
Mechanosensitive dynamics at the fertilisation synapse
RUPRECHT Verena (AUSTRIA)
Cell and Tissue Dynamics Group - Centre for Genomic Regulation (CRG) - Barcelona - SPAIN
PAULI Andrea (GERMANY)
Pauli Laboratory - IMP - Research Institute of Molecular Pathology - Vienna - AUSTRIA
LIU Yan-Jun (CHINA, PEOPLE'S REPUBLIC OF)
Shanghai Institute of Cardiovascular Diseases,and Institutes of Biomedical Sciences - Fudan University - Shanghai - CHINA, PEOPLE'S REPUBLIC OF
Fertilization, the fusion of two highly specialized cells, the egg and sperm, marks the beginning of life of all sexually reproducing organisms. Despite its fundamental role, we still understand very little about how sperm-egg interaction is controlled. Research so far has mostly focused on identifying proteins that mediate gamete attachment and fusion while largely neglecting the fact that fertilization is an inherently dynamic process, during which the two gametes get together, interact and fuse. Although the sperm is in general viewed as the ‘active’, motile partner during gamete encounter and interaction, a key open question remains whether the egg does also play an ‘active’ role in the fertilization process, e.g. by generating forces that might actively engulf the sperm.
To tackle this fundamental gap in our knowledge, we propose a two-pronged, cross-disciplinary approach to 1) characterize the mechanosensitive properties of the egg before, during and after fertilization by state-of-the-art biophysical techniques; and 2) pioneer the development of a bottom-up fertilization assay that we term ‘synthetic fertilization synapse’. As such, we envision to reconstitute sperm-egg interaction dynamics in a simplified in vitro system, in which we will replace the sperm by specific proteins in micro-structured lipid bilayers to study the impact of ligand mobility, number, and spatio-temporal organization on egg activity. In combination, we will use a controlled micro-confinement-based force actuator approach to perform global and local mechanical stimulation of the egg. Mechano-chemical responses of the egg will be measured by state-of-the-art high-resolution imaging and quantitative force measurement techniques. Zebrafish gametes will serve as main model systems, which will be complemented by experiments in mouse gametes. Tackling this highly challenging problem of the biophysical control of fertilization becomes only feasible by combining our different core expertise in an interdisciplinary approach.
Our research will provide fundamental insights into the dynamics of sperm-egg interaction and its mechanosensitive regulation. These insights promise to transform our currently rudimentary knowledge of the mechanism of fertilization.
2020
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Long-Term Fellowships - LTF
Deciphering the principles of enhancer cooperativity
LOUBIERE Vincent (FRANCE)
- Research Institute of Molecular Pathology - Vienna - AUSTRIA
STARK Alexander (Host supervisor)
Metazoan development relies on tightly regulated gene expression patterns. Hence, the regulatory landscapes of developmental genes are complex and often contain several simultaneously active enhancers. Recent studies reported that the combined enhancer activities in such loci can either be additive, super-additive or sub-additive compared to the sum of the individual activities. Yet, the principles that might govern enhancer cooperativity remain elusive.
To fill this gap, I propose measuring the activity of large collections of systematically paired developmental enhancers using STARR-Seq (500x500 enhancers), which was developed in my host lab to map individual enhancers genome-wide. I expect to identify an unprecedented number of additive, super- and sub-additive enhancer pairs and to reveal the sequence features associated with these distinct behaviors. To test all the genomic elements that could potentiate and/or interfere with developmental enhancer activity, I will use another STARR-Seq variant in which selected developmental enhancers will be individually paired with a comprehensive library of genomic DNA fragments (1xall elements). This will address how housekeeping enhancers, which form a functionally distinct class of enhancers, and other types of genomic elements impact developmental enhancer activities.
Finally, I will validate my results in situ using CRISPR/Cas9 genome editing and test whether the genes’ endogenous regulatory landscapes influence enhancer cooperativity. Overall, this original approach will address a key aspect of developmental gene regulation which, despite its relevance for the study of development and pathogenesis, remains elusive.
2020
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Long-Term Fellowships - LTF
Immune-vascular crosstalk in the postnatal period
MADEIRA Silvia (PORTUGAL)
Department of Oncology - University of Lausanne - Lausanne - SWITZERLAND
PETROVA Tatiana (Host supervisor)
The neonatal period is witness to fast physiological changes. The, up until birth, largely sterile environment becomes colonized by microbes, crucial for imprinting durable and specific immune responses, a period named “window of opportunity”. Postnatal immune imprinting involves extensive inter-organ trafficking of immune cells, and hence their interaction with endothelial cells of blood and lymphatic vessels. Still, to date virtually nothing is known about immune-vascular cross talk during postnatal period and the role of endothelial cells in immune imprinting.
By using a mouse model that expresses a photoconvertible fluorescent protein, I will first characterize the immune subsets trafficking from gut, an essential organ for postnatal immune education, to other organs. Second, I will study the molecular changes in endothelial cells in this neonatal period to understand how this affects inter-organ communication and the pre-programming of long-lasting immune responses. This will be done by flow cytometry, high resolution 3D imaging and single cell RNA sequencing. Moreover, while there is a significant knowledge on the impact of environmental factors such as nutrition, exposure to antibiotic and farm animals on future health, much less is known about postnatal education of blood and lymphatic vasculature. Accordingly, I will investigate the impact on diet and microbial colonization in the neonatal period and their effects on both immune and vascular components.
Altogether, I wish to unveil how early life events impact the immune-vasculature crosstalk and future health imprinting, thus helping to unlock intricate disease mechanism and their prevention in the future.
2020
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Grant Awardees - Program
T cell crowd control
TEXTOR Johannes (GERMANY)
Dept. of Tumour Immunology - Radboud University Medical Center - Nijmegen - NETHERLANDS
MANDL Judith (AUSTRIA)
Dept. of Physiology and Complex Traits Group - McGill University - Montreal - CANADA
PARISI Daniel (ARGENTINA)
Computer Engineering Dept. - Buenos Aires Institute of Technology - Buenos Aires - ARGENTINA
T cells are key effectors of adaptive immunity that are constantly moving, can enter most tissues, and operate in large crowds. Millions of densely packed T cells continuously roam through lymphatic tissue in search of foreign antigen; activated T cells divide vigorously, flock to tissues, mount local immune responses to pathogens or cancer cells, and remain there to guard against further intrusions.
Crowding is normally expected to deter motion and lead to jamming, an effect confirmed in very diverse systems ranging from pedestrians and vehicular traffic to cellular monolayers and granular material. Yet T cells defy this general principle and are capable of fluid motion even in extremely dense environments such as lymphatic tissue and the epidermis, where there is no apparent room to maneuver. How they achieve this is unclear: although novel microscopy modalities can visualize migrating T cells in living tissue, studies of T cell movement have primarily focused on individual or few cells and have not addressed potential crowding effects.
We hypothesize that (1) T cells have evolved to cooperate effectively in large groups and avoid crowding issues, such that (2) impaired T cell crowd operation is largely confined to anomalous tissue environments such as tumors. Here, we aim to unravel the mechanisms that facilitate fluid, “jam-free” motion of densely packed T cells, and determine in which situations T cell traffic might nevertheless be disturbed by emerging detrimental crowding effects.
We will study T cell crowds in a wide range of conditions in silico, in vitro and in vivo: we will (1) conduct simulations to predict how T cell crowds operate in challenging conditions and which emerging crowd behavior is expected; (2) design microfluidic devices to expose T cell crowds to hallmark crowding scenarios, identify molecules involved in cellular crosstalk within crowds, and identify transcriptional signatures associated with efficient crowd operation; (3) examine T cell crowds in human and mouse tissues to test whether dynamic or static patterns indicating jamming can be confirmed in physiological or pathological conditions in vivo.
Thus, by combining our unique joint expertise in crowd dynamics, immunology, and computational biology, we will shed light on how T cell crowds, a system quite unlike any other many-particle system studied so far, maintain motion with such remarkable efficiency in many conditions and what it would take to disrupt their smooth flow.
2020
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Long-Term Fellowships - LTF
Interplay between membrane tension and branched actin network dynamics during cell migration
MEHIDI Amine (FRANCE)
Department of Biochemistry - University of Geneva - Geneva - SWITZERLAND
AUMEIER Charlotte (Host supervisor)
Cell motility is an integrated process implicated in many cellular functions such as embryogenesis, immunological response, wound healing, and growth cone path finding. For a long time, the study of cell migration has mainly focused on the observation of molecular components responsible for the formation of cell protrusion: actin networks and actin regulatory proteins. Recent studies propose that membrane biophysics, in particular membrane tension, could control actin network formation and cell migrations. Thus, in this project I propose to study the interplay between membrane tension and actin networks during cell migration. To do so, I will use a tension-sensitive fluorescent probe (FliptR probe) to measure membrane tension, together with a cell permeable fluorogenic F-actin label (SiR-actin) suitable for live labelling of the actin cytoskeleton. Using these probes, I will measure the local membrane tension variations during cell migration and monitor how these affect and/or are affected by actin cytoskeleton. By combining these approaches with the cutting-edge technique of adhesion protein micro-patterning, I will create a controlled and reproducible environment to finely tune cell migration. This will allow us to understand how the cellular environment affects the interplay between membrane tension and actin cytoskeleton. All together, I propose an innovative approach that will enable us for the first time to study the impact of local membrane tension on cell migration. The findings of this project will shed light into the cell migration, actin and lipid membrane fields.
2020
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Long-Term Fellowships - LTF
Macrophage – intestinal epithelial cell crosstalk in the integration of cell death and tissue repair
MELI Alexandre (CANADA)
Department of Immunobiology - Yale University - New Haven - USA
ROTHLIN Carla (Host supervisor)
The intestinal epithelium is a mucosal tissue reliant on its regenerative capacity as it is perpetually exposed to cell death whether it be during homeostasis or insult. Defective regeneration of the epithelium is associated with multiple diseases such as Intestinal Bowel Disease. Macrophages can act to sense damage and enhance tissue repair in the gut. Whether they can integrate the recognition of dying cells with intestinal epithelial regeneration remains unknown. We previously reported that the recognition of apoptotic cells by macrophages enhances their capacity to promote tissue repair. However, depending on the nature of intestinal injury, intestinal cells can undergo divergent cell death modalities including apoptosis, necroptosis and pyroptosis. Thus, we propose a model wherein macrophages directly participate in the integration of cell death with tissue repair. We aim to characterize cell death modalities, including that of stem cells, in models of intestinal injury. We additionally plan to identify the relevant cell death receptors for macrophage detection of apoptotic, necroptotic or pyroptotic cell death and correlate these findings with regeneration/repair or its failure during disease. Current treatment strategies focus on resolving inflammation during intestinal disease instead of enhancing regenerative responses of the epithelium. Thus, uncovering the nature and consequence of cell death in the gut may provide valuable insight into the treatment of gastrointestinal diseases.
2020
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Long-Term Fellowships - LTF
Regulation of X-chromosome inactivation during metatherian development
MENCHERO Sergio (SPAIN)
Sex Chromosome Biology Laboratory - The Francis Crick Institute - London - UK
TURNER James (Host supervisor)
Sex determination through the X and Y chromosomes is among the novelties that characterise mammals. The genetic dimorphism generated by the different content of sex chromosomes between males (XY) and females (XX) had led X-dosage compensatory mechanisms to arise. One of the two X chromosomes in females needs to be silenced in order to avoid a double dose of X-related genes in females as compared to males. The way to achieve X-chromosome inactivation (XCI) has evolved differently between two mammalian infraclasses: eutherians (placentalia) and metatherians (marsupialia). A series of epigenetic modifications and the coordinated activity of lncRNAs led by the master regulator Xist, are key for XCI in eutherians. In marsupials, Xist is not conserved and little is known about how this process occurs. James Turner’s group found that another lncRNA, namely RSX, is specifically expressed from the inactive X in the opossum Monodelphis domestica and may drive XCI in metatherians. In this project, I will investigate the epigenetic mechanisms responsible for achieving XCI in the opossum during embryonic development. Specifically, I will focus on the role that repressive histone modifications play in the germline and in the early embryo to regulate imprinted XCI. I will also interrogate if the link between pluripotency and biallelic expression of X-linked genes is maintained in the opossum and how the regulatory landscape of Xist and RSX has evolved between eutherians and metatherians. This project will be important to gain insight into how genomic imprinting and the epigenetic landscape is established in metatherians and how it has evolved since the divergence from eutherian mammals.