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2021 -
Long-Term Fellowships - LTF

Molecular determinants of selective viral RNA recognition by MDA5

HERRERO DEL VALLE Alba (SPAIN)

Department of Medicine - University of Cambridge - Cambridge - UK

MODIS Yorgo (Host supervisor)
Mammalian cells can recognize the presence of a viral infection by sensing the viral nucleic acids in the cytosol. Viral RNAs activate a specific set of pattern-recognition receptors called RIG-I-like receptors (RLRs). Among these, melanoma-differentiation associated gene 5 (MDA5) selectively recognizes long dsRNAs. Upon recognition of the viral genetic material, RLRs activate an inflammatory type I interferon response. This response needs to be sensitive and specific as its aberrant activation has been linked to autoimmune and autoinflammatory diseases. In the case of MDA5, single nucleotide polymorphisms in IFIH1, the gene encoding MDA5, have been associated with autoimmune diseases including Aicardi-Goutières syndrome, Singleton-Merten syndrome and other interferonopathies where interferon is chronically produced. However, how these mutations lead to the aberrant expression of interferon is still unknown. Besides, it is still poorly understood how MDA5 distinguishes between cellular and viral RNA and how naturally occurring RNA modifications affect the selectivity of MDA5. This work will focus on how MDA5 recognizes viral RNA in the normal and disease-associated contexts. Different variants of MDA5 will be assessed and their dsRNA-activated interferon signaling activities will be compared. The cryo-EM structures of MDA5 filaments will be determined with the aim of understanding at the atomic level how RNA modifications and mutations in MDA5 alter its recognition of dsRNA. This project will provide invaluable insights into viral RNA recognition in health and disease, and will suggest new immunomodulatory strategies.
2021 -
Grant Awardees - Program

Structural damage to axons resulting from repetitive mechanical motion

HESS Henry (GERMANY)

Biomedical Engineering - Columbia University - New York - USA

KAKUGO Akira (JAPAN)

Faculty of Science - Hokkaido University / Graduate School of Science - Sapporo - JAPAN

RAFFA Vittoria (ITALY)

Department of Biology - Università di Pisa - Pisa - ITALY

SHEFI Orit (ISRAEL)

Faculty of Engineering - Bar-Ilan Institute of Nanotechnology and Advanced Materials - Ramat Gan - ISRAEL

Biological structures have evolved to very efficiently generate, transmit, and withstand mechanical forces. Biological examples have inspired mechanical engineers for centuries and led to the development of critical insights and concepts. For example, “tensegrity” refers to the emergence of stability as a result of a balance of tensile and compressive elements in a mechanical structure. It was inspired by the human musculoskeletal system, applied to architectural designs, and returned to biology as a framework to understand cellular mechanics. However, progress in the engineering discipline of mechanics also raises new questions about biological structures. The past decades have seen the increasing study of failure of engineered structures, and its origin in processes such as materials fatigue. Some tissues, such as the spinal cord, are formed from long-lived nerve cells which maintain their function over the entire lifetime of the organism. How do these cells maintain their operation despite being constantly subjected to mechanical stresses? How do the mechanical stresses degrade intracellular structures, and what mechanisms are activated to effect repair? These are the fundamental biological questions we aim to address. We will mimic the repetitive mechanical motion and study how it damages internal structural components in the long extensions of nerve cells and which repair mechanisms contribute to maintaining their health. Specifically, we will: (1) develop a novel experimental setup to exert thousands of cycles of stretching and bending deformations on the nerve cell extensions, (2) characterize the structural damage to them, (3) characterize the functional damage to them, (4) identify the repair mechanisms employed by the cell to mitigate and reverse the mechanical damage, and (5) integrate the obtained information into a coherent model. The newly formed team is composed of experts in biomechanics, materials science and nanotechnology, neuroscience and regenerative medicine, and will combine experimental and modeling approaches. Overall, we take an engineering perspective and apply it to cell biology by asking not “How does it work?” but “How does it keep working for so long?”. The obtained insights will inform our understanding of the mechanical aspects of maintaining cellular health, inspire new biomimetic approaches to engineering, and yield a better appreciation of the cell as a “self-repairing machine”.
2021 -
Grant Awardees - Program

Understanding the cellular mechanics of coral bleaching

HU Ke (CHINA, PEOPLE'S REPUBLIC OF)

Center for Mechanisms of Evolution - Arizona State University - Tempe - USA

INABA Kazuo (JAPAN)

Shimoda Marine Research Center - University of Tsukuba - Shizuoka - JAPAN

Mutualistic and parasitic intracellular symbionts have an enormous impact in the global ecosystem as well as on the health and behavior of their hosts. Coral bleaching, a major global ecological crisis, is caused by the massive loss of the symbiont dinoflagellate Symbiodinium from its coral hosts. Sustained coral bleaching leads to coral death, destroying an essential foundation of the marine ecosystem. While the importance of Symbiodinium spp in the marine ecosystem has long been established, the cellular mechanics of how the intracellular association with their hosts is established and dissolved is not understood. To tackle this problem, the joint team of the Hu Lab (Arizona State University, U.S.A.) and the Inaba Lab (Shimoda Marine Research Center, University of Tsukuba, Japan) will combine our expertise in cell biology, microscopy, parasitology, evolution biology and marine biology. We will use an evolution-guided strategy to test whether two seemingly incongruent processes - the exodus of Symbiodinium from cnidarians and the egress of apicomplexan parasites from mammalian cells- share a common evolutionary origin and cellular mechanics. Our work will reveal the nature of the force driving exodus of symbiont from coral, and develop molecular genetic tools that are essential for investigating the fundamental biology of the Symbiodinium-cnidarian partnership.
2021 -
Long-Term Fellowships - LTF

Molecular dynamics of size sensing at the single cell level

KAPADIA Nitin (CANADA)

Cell Cycle Laboratory - The Francis Crick Institute - London - UK

NURSE Paul (Host supervisor)
Cells have strict control over their size to ensure proper cell physiology. They also have ways to correct for deviations, referred to as cell-size homeostasis, leading to a very narrow distribution in cell size at division. Although some of the genes involved in this process have been identified, the underlying molecular mechanism has remained elusive. One possibility is that the cell can “sense” its size through a protein whose concentrations are related to cell-size - known as the sizer model. However, this would not completely explain the fact that diploid cells are approximately twice the size of haploids, suggesting that ploidy also plays a role - something that has not garnered a lot of attention in the field. Live-cell fluorescence microscopy is well-suited to address these issues because we can directly visualize the dynamics and localization patterns of sizers, along with cell-size, and quantify these characteristics. I propose to develop a live single-cell fluorescence microscopy approach using a microfluidics device that allows mother cell lineages to be tracked across multiple generations, for use with haploid and diploid strains of the unicellular eukaryotic organism, Schizosaccharomyces pombe. This will allow me to measure protein levels of sizer candidates and their localization, along with cell length, across single lineages. This information could reveal long-term dynamics and correlations between sizer candidates and cell-size, and provide insight into the molecular mechanisms governing cell-size homeostasis and the role that ploidy plays in governing cell-size control within eukaryotes.
2021 -
Long-Term Fellowships - LTF

Elucidating key neuroinflammation pathway(s) involved in the brain of Drosophila

KHAN Anzer (INDIA)

Global Health Institute - École Polytechnique Fédérale de Lausanne - Lausanne - SWITZERLAND

LEMAITRE Bruno (Host supervisor)
Neurodegenerative disorders are primarily defined by neuronal loss within the central nervous system. Traditionally, research on neurodegeneration has focused on neurons, but recently a prominent role for the innate immune system has been proposed. Chronic inflammation, a feature observed in many neurodegenerative contexts, is now suspected to drive disease progression. The study of neurodegenerative disease is made complex by the late onset of neurodegenerative symptoms and difficulties in accessing the brain, amongst other challenges. In recent years, Drosophila has emerged as a powerful model to study neurodegeneration, and several models mimicking human diseases including Alzheimer’s and Parkinson’s have been developed. Here, I intend to elucidate how the innate immune system contributes to neurodegeneration in Drosophila. My first objective will be to provide a broad description of the head immune responses and decipher whether the Drosophila brain possesses a dedicated immune system with its own peculiarities. My second objective will be to characterize the immune response in the brain during neurodegeneration. Antimicrobial peptides (AMPs) have recently been implicated in neurodegeneration in flies. My third objective will be to decipher the contribution of of AMPs to disease progression, using newly generated AMP mutants Collectively, my study will provide a foundation for how neuroimflammatory pathways regulate the health of neurons and their role in neurodegenerative diseases, and it will also help us to understand whether inflammation is a driver of or a response to neurodegeneration.
2021 -
Long-Term Fellowships - LTF

The role of cancer-induced hematopoietic stem cell activation in the development of atherosclerosis

KISS Máté (HUNGARY)

Department of Pathology and Immunology - University of Geneva - Agora Cancer Center Lausanne - Lausanne - SWITZERLAND

PITTET Mikael (Host supervisor)
The increasing number of long-term cancer survivors necessitates a better understanding of the late-onset health effects of cancer. Epidemiological studies show that survivors of cancer have an increased risk of cardiovascular disease compared to the general population; however, the underlying mechanisms remain unclear. Activation of hematopoietic stem cells (HSCs) for enhanced production of disease-promoting myeloid cells is a key driver of both tumor and atherosclerosis progression. Therefore, cancer-induced alterations in hematopoiesis may also affect coexisting atherosclerosis. In addition, tumors may induce long-term epigenetic reprogramming in HSCs, sensitizing them for systemic inflammatory signals during atherosclerosis after curative treatment of cancer. In the proposed project, I will determine whether cancer can induce persisting changes in HSCs, leading to increased myelopoiesis and exacerbated cardiovascular disease. To this end, I will combine transcriptomic and epigenomic analyses to characterize tumor-induced changes in HSCs that may influence the hematopoietic response to secondary stimuli. By inducing atherosclerosis in tumor-bearing mice or mice transplanted with cancer-primed HSCs, I will determine the role of tumor-induced HSC activation in vascular inflammation. Finally, by testing deletion of candidate receptors in the hematopoietic compartment, I aim to identify tumor-induced systemic factors driving HSC activation. This work will provide fundamental insights into the long-term impact of cancer on the immune system and its consequences on atherosclerosis development with implications for the clinical care of the growing cancer survivor population.
2021 -
Grant Awardees - Program

Revealing the interplay of genetics and biomechanics underlying butterfly scale morphogenesis

KOLLE Mathias (GERMANY)

Department of Mechanical Engineering - Massachusetts Institute of Technology - Cambridge - USA

NADEAU Nicola (UK)

Dept. of Animal and Plant Sciences - The University of Sheffield - Sheffield - UK

WILTS Bodo (GERMANY)

Department of Chemistry and Physics of Materials - University of Salzburg - Salzburg - AUSTRIA

During the final stage of metamorphosis, butterfly wings sprout with hundreds of thousands of scales, each formed by a single cell and carrying precise nanostructural motifs. Delicate control of scale structure on the single-scale level determines multiple functions of the wing, including brilliant colors, water repellency, thermoregulation, and lift generation. Despite these functions being of great interest to biologists and engineers alike, we only have limited knowledge of the mechanisms underlying scale formation. This project aims to decipher the processes underlying butterfly scale morphogenesis using newly developed methods for observing the scales while they are forming in the chrysalis, combined with biomechanical modeling, molecular analysis, genetic manipulation of scale formation, and nano-scale electron-microscopic analysis of formed scale morphologies. To understand the coordination across different morphological features, the characterization of the temporal changes during stages of development is critical. By integrating these different approaches, we will shed light on the mechanical effects, biomolecular constituents, and genetic factors that drive the temporal and spatial coordination during wing scale development. The result of this collaborative interdisciplinary effort between biologists, materials scientists, and engineers will be a complete time-resolved picture of scale structure formation, paired with information about the landscape of molecular constituents in critical developmental phases, a deeper understanding of the biomechanical phenomena, and a clearer view on the interplay between specific genetic components, their effect on the scales’ biochemistry and its influence on critical biomechanical interactions. We will test our understanding through genetic manipulation and through time-sensitive inhibition of structural components. The deeper understanding of biological formation of functional material architectures gained through this effort will form the basis for future targeted initiatives aimed at translating structure formation principles from biological systems into synthetic functional materials for applications in optics, sensing, biomedical devices and textile technology, sustainable paints and coatings, and augmented reality infrastructure.
2021 -
Long-Term Fellowships - LTF

How transcriptional and epigenetic networks shape lung-resident memory T cells and tissue immunity

LERCHER Alexander (AUSTRIA)

Laboratory of Virology and Infectious Disease - Rockefeller University - New York - USA

RICE Charles M. (Host supervisor)
Immunological memory is a cardinal feature of adaptive immunity and forms the molecular basis of vaccines. Memory T cells provide long-term antigen-specific protection against intracellular pathogens. Circulating memory T cells provide de-centralized immune surveillance, whereas tissue-resident memory T cells (Trm) provide highly potent immune responses on-site that are tailored to the tissues in which they reside. Trm cells are highly abundant in barrier sites and enable rapid immune responses upon antigen re-encounter and are thus an integral part of the first line of defense against pathogens. In the lung, Trm cells are important to fend off recurring respiratory pathogens, but they are hampered by poor longevity. Here, I propose to combine disease-relevant infection model systems with cutting-edge single cell technologies to chart a map of transcriptional and epigenetic networks that govern Trm cell ontogeny and function in the lung. Genetic perturbation and molecular dissection of putative regulators of Trm cell identity in vivo will help to unravel novel therapeutic targets to boost Trm cell formation and/or functionality. Employing superinfection models with heterologous pathogens will help to expand those findings beyond antigen-specific immune responses. Together, the insights gained in this interdisciplinary project will broaden our understanding of adaptive tissue immunity towards respiratory pathogens and advance our portfolio of therapeutic prevention or intervention strategies.
2021 -
Grant Awardees - Program

Teratology in microfossils as a proxy for understanding mass-extinctions through time

LOMAX Barry (UK)

Dept. of Agriculture & Environmental Science - University of Nottingham - Nottingham - UK

LOOY Cindy (NETHERLANDS)

Dept. of Integrative Biology - University of California, Berkeley - Museum of Paleontology - Berkeley - USA

VAN DE SCHOOTBRUGGE Bas (NETHERLANDS)

Dept. of Earth Sciences - Utrecht University - Utrecht - NETHERLANDS

VANDENBROUCKE Thijs (BELGIUM)

Department of Geology - Ghent University - Ghent - BELGIUM

Mass-extinction events in Earth history can provide us with crucial baselines by which ongoing biodiversity loss can be compared and its selectivity calibrated. All mass-extinction events are connected to extreme perturbations of the carbon cycle, including changes in greenhouse gas concentrations and associated global warming/cooling. These major changes in the carbon cycle are thought to be driven by interconnected episodes of widespread volcanism, rapid increase or burning of biomass, burial, erosion or oxidation of carbon, destabilization of methane from the seafloor and permafrost, and marine anoxia. A recently discovered phenomenon associated with mass-extinction events is an increase of teratological microfossils (pollen, spores, organic-walled phyto- and zooplankton) with aberrations in morphology and texture. These malformed fossils allow us to make direct inferences about the proximate mechanisms behind these biotic crises. Unique in the fossil record, these tell-tale signatures co-occur in, and can be recovered from both the marine and terrestrial realms, allowing for the integration of these records and a search for commonality. With this interdisciplinary project we aim to test a set of interrelated hypotheses that link malformation to either metal toxicity (Hg, Cd, Ni, Pb), or increased UV-B radiation due to ozone loss, or to environmental stress related to climate change. Here, we propose to use these microfossils and their modern analogues in experimental and field settings to explore the true potential of teratology as a proxy to test, integrate and refine the many existing models for biotic crises across time and space. The deep time perspective is provided by work packages led by Ghent University and Utrecht University working on Paleozoic and Mesozoic events characterized by the presence of abundant malformed microfossils reflecting both marine and terrestrial ecosystems. Planned work will tease out the relative influence of metal toxicity related to marine anoxia and volcanic activity from geochemical and micropaleontological analyses of core and outcrop material complemented by studies of modern analogs. Work at UC Berkeley and University of Nottingham, focusing on the role of UV-B radiation, metals and temperature, will ground-truth observations from deep time via growth experiments using nearest living relatives.
2021 -
Cross Disciplinary Fellowships - CDF

Dynamics of active matter in complex and heterogeneous habitats

MARTÍNEZ CALVO Alejandro (SPAIN)

Department of Chemical and Biological Engineering - Princeton University - Princeton - USA

DATTA Sujit (Host supervisor)

Bacteria can self-organize into a myriad of morphologies and thrive in diverse ecosystems by developing survival strategies that protect the community from external threats. It has been recently proposed that understanding the collective mechanisms of prokaryotic cells could pave the way to fathoming the strategies developed by eukaryotic communities, yet this connection remains unclear. Both systems grow in heterogeneous habitats, namely organs or tissues. In this project, through experiments and mathematical modeling I aim to unravel the collective behavior and cooperativeness that bacteria and eukaryotic cells have in common in complex environments. To this end, several bacterial species, as Escherichia coli and Pseudomonas aeruginosa, and MDCK eukaryotic cells, will be cultivated in different 2D and 3D media mimicking realistic conditions, exposing them also to different external stimuli and heterogeneities, namely chemical and thermal gradients, shear flows, or mechanical forcing. From the theory side, I will employ and derive continuum nematic models, and active vertex models in the case of eukaryotic systems. The interplay between experiments, theory and simulations will be essential to understand the underlying cooperative mechanisms and the collective response of active matter in competitive and heterogeneous habitats, a research direction that remains almost virgin to date. Natural outcomes stemming from this proposal are a better understanding of cancer pathogenesis and antibiotic resistance, or the production of living and synthetic meta-materials at our whim by controlling the morphogenic response of active systems.

2021 -
Long-Term Fellowships - LTF

Understanding adaptability of egg-laying behavior in Aedes aegypti

MOHAMMED GARBA Yunusa (NIGERIA)

Department of Zoology - University of British Columbia - Vancouver - CANADA

MATTHEWS Benjamin (Host supervisor)
Aedes aegypti mosquitoes are endemic to many regions throughout the world and are vectors of arboviral pathogens that cause Dengue fever, yellow fever, Chikungunya, and Zika. Ae. aegypti are supremely adaptable and can be found breeding in a wide variety of urban and rural aquatic sites associated with human habitation, likely requiring physiological and behavioral adaptability to thrive in these diverse environments. Ae. aegypti decide where to lay eggs based on sensory cues in liquid water to maximize survival of their offspring. The aims of my proposal are to 1) Establish colonies of Ae. aegypti derived from wild strains that exhibit differential preference for egg-laying water mixtures. 2) Perform neuronal imaging to quantify differences in sensory neuron tuning to different egg-laying water mixtures. 3) Use RNA-seq to quantify any changes in expression or sequence of chemoreceptor gene function across tissues involved in egg-laying in strains with divergent preference. This work will build on previous work by my host supervisor and my PhD training in neuroscience and chemical ecology to understand egg-laying preference in Ae. aegypti at multiple biological levels and also to determine why Ae. aegypti (and not other species of mosquitoes) have become so intertwined with human settlement. I will also build genetic tools that will allow researchers to probe many aspects of mosquito biology to support critically important mosquito control efforts around the world.
2021 -
Grant Awardees - Program

The aphrodisiac gut: defining the factors promoting yeast mating within insect intestines

NEW Elizabeth (AUSTRALIA)

School of Chemistry - University of Sydney - University of Sydney - AUSTRALIA

POLIN Marco (ITALY)

Mediterranean Institute For Advanced Studies (IMEDEA) - CSIC-University of Balearic Islands - Esporles - SPAIN

SEGRE' Daniel (ITALY)

Graduate Program in Bioinformatics - Boston University - Boston - USA

STEFANINI Irene (ITALY)

Department of Life Sciences and Systems Biology - University of Turin - Turin - ITALY

Saccharomyces cerevisiae (Sce) has seen widespread use by humans throughout history for winemaking, brewing, and bakery. However, a process fundamental for this yeast’s evolution still remains only partially understood: interstrain mating (outbreeding), which potentially results in strains bearing new genomic settings and fitness. While outbreeding is easily achievable in laboratory settings, it is extremely rare in nature. In fact, we have only recently discovered the first environment where it can occur: within wasp guts. Comprehending what makes the insect gut an environment suitable for Sce mating would provide us with a better understanding of Sce evolution and expand our knowledge beyond the unnatural lab settings. Outbreeding is achieved through a multi-step process encompassing sporulation, germination, ascus break, and mates encounter. These steps may be promoted within wasp guts thanks to the sequence of drastically different chemical and mechanical stresses peculiar to this environment. We have set up a team of experts in all the fields necessary to tackle this hypothesis: microbiology, genetics, chemistry, physics, and computational biology. We will carry out in vivo experiments to assess the wasp gut environment by using dedicated sensors and Sce genes fundamental for germination and sporulation in this environment. These data will be instrumental to develop a genome-scale mathematical model exploring yeast genetics, metabolic and environmental features favoring germination and sporulation. In vitro high-throughput assays assessing both the yeast response and metabolites measured by dedicated intra- and extra-cellular sensors will provide further data to calibrate the model. Physical forces required for Sce ascus break or mate encounter will be measured through up-to-date biophysical techniques: cylindrical Couette chambers, micropipette force sensors, and microfluidic droplets. We will bring together the information that we gather about each stage to develop microfluidic devices emulating the structure and physiology of wasp guts and investigate there the entire process leading to outbreeding. This project will unveil the key factors of Sce evolution by providing fundamental insights on the biological mechanisms leading to outbreeding in natural settings, thus potentially revolutionizing our current understanding of the process.
2021 -
Long-Term Fellowships - LTF

Understanding the regulation of neuropathology-associated protein and RNA repeats in Dictyostelium

NGUYEN Tu Anh (VIETNAM)

Department of Biology - Whitehead Institute for Biomedical Research - Cambridge - USA

JAIN Ankur (Host supervisor)
Expansion of short nucleotide repeats is the cause of over 30 inherited neurological diseases. These expansions could result in neurotoxicity through a loss of protein function or accumulation of misfolded repeat-containing proteins. Repeating-containing RNA, which accumulates in aberrant nuclear foci, can also be a driver of pathogenesis by sequestering RNA processing proteins and producing toxic peptides through non-canonical translation. Recently, RNA containing these disease-associated repeats (DARs) has been demonstrated to intrinsically undergo phase transition to form an aggregated state through multivalent base-pairing, providing a model for the mechanism of RNA foci formation in repeat expansion diseases. The genome of the social amoeba Dictyostelium discoideum contains an exceptionally high number of short nucleotide repeats, many of which occur in coding regions and resemble human DARs. My work will develop Dictyostelium as a model for studying evolutionarily derived mechanisms which keep DAR-containing proteins and RNA from becoming pathogenic. Specifically, this proposal presents experimental strategies for identifying factors which prevent the aggregation of DAR-containing proteins and RNA, and non-canonical translation of DAR-containing RNA. The efficacy of these factors in suppressing DAR toxicity will be investigated in mammalian cells and animal disease models. Besides their relevance to disease pathogenesis and therapeutic potential, insights derived from the proposed study will also shed light on basic principles regulating RNA and protein homeostasis.
2021 -
Cross Disciplinary Fellowships - CDF

Compaction and organization of macroH2A containing heterochromatin in therapy-induced senescence

OU Arnold (AUSTRALIA)

Laboratory of Genome Architecture and Dynamics - Rockefeller University - New York - USA

RISCA Viviana (Host supervisor)

Chemotherapy-induced senescence (TIS) is an alternative form of senescence, which is triggered by inhibiting the cell-cycle (senescence after growth arrest or SAGA) with CDK4/6 inhibitors, such as palbociclib. MacroH2As (a non-canonical histone variant of H2A) are enriched in during senescence and is believed to maintain heterochromatin and repression of cell cycle genes. The nucleosome-nucleosome interactions of macroH2A, which influence compaction and transcription, remains largely unknown. This is mainly due to the limitation of current techniques and the challenges which heterochromatin pose. However, the structural mechanisms of macroH2A and its subtypes (1.1, 1.2, and 2) play to maintain stable gene repression during senescence is largely unknown. Using a TIS model liposarcoma cell line and by developing chromatin targeted probes to induce spatially correlated breaks to infer structural information on the nanoscale (tri-nucleosome) level, I will investigate the structural-function relationship in heterochromatin and macroH2A in SAGA induced liposarcoma cells. The findings of this work will provide a better insight into this novel mode of senescence (TIS) by understanding how chromatin reorganization and cell growth genes are repressed and maintained by macroH2A.

2021 -
Long-Term Fellowships - LTF

Use of Shigella-septin interactions to explore biophysical cues in cell-autonomous immunity

OZBAYKAL-GULER Gizem (TURKEY)

Department of Infection Biology - London School of Hygiene and Tropical Medicine - London - UK

MOSTOWY Serge (Host supervisor)
Shigella is an important human pathogen responsible for 164,000 deaths per year, and cases of antimicrobial resistance are rising. In the lab, Shigella has emerged as a paradigm of cellular microbiology whose investigation has enabled landmark discoveries in infection and cell biology. Septins, a poorly understood component of the cytoskeleton recognised for their roles in cell division, can entrap cytosolic Shigella in cage-like structures for host defence. For cage entrapment, new work has shown that septins recognise micron-scale curvature presented by Shigella. Despite recent insights, the physical and molecular determinants of septin recruitment and cage assembly required for Shigella entrapment are mostly unknown. My proposal will investigate biophysical cues that underlie Shigella-septin interactions, and illuminate their role in cell-autonomous immunity. Using state-of-the-art fluorescence microscopy techniques, I will first investigate the spatial dynamics of Shigella virulence proteins and cell biophysics in broth culture and during septin cage entrapment in vitro using purified proteins. Next, I will resolve the impact of biophysical cues presented by Shigella which trigger cell-autonomous immunity during infection of human epithelial cells. Together, these integrative experiments will provide valuable insights about biophysical cues sensed by cell-autonomous immunity to defend against intracellular bacterial pathogens, bridging our views of biophysics and host defence. The outcomes of my research plan are expected to discover novel concepts in infection biology and cellular homeostasis, and may inspire septin-based approaches to counteract bacterial infection.
2021 -
Long-Term Fellowships - LTF

The fate of functional chromatin states through mitosis: a single-cell analysis

PALDI Flora (HUNGARY)

Department of Genome Dynamics - Institut de Génétique Humaine - Montpellier - FRANCE

CAVALLI Giacomo (Host supervisor)
Cellular identity is defined by the expression of specific gene sets. Once established, the information to maintain gene expression programs is stored in alternative chromatin states, which are thought to be propagated through cell divisions to maintain cellular identity. However, although cellular memory is widely accepted as an important aspect underlying development, empirically it is yet to be demonstrated to exist at the single-cell level. Indeed, one possibility is that functional chromatin states are epigenetically propagated through mitosis, and a cellular memory operates at the single-cell level. Alternatively, cell fates could be inherently probabilistic, depending on the distribution of regulatory factors between nascent cells. In this project I propose to investigate this topic by combining advanced imaging, single-cell multi-omics and prospective lineage tracing. To study molecular states in cell pedigrees I will take separate approaches, using mouse embryonic stem cells as model. First, to test how much of the transcriptional identity of a parent is maintained in progenies, I will analyse transcriptional states of individual cells in traced lineages. Second, to understand if parental chromatin structures that underlie locus activity can be reproduced following mitosis, I will study similarities in locus conformation in related cells. Finally, I propose to investigate how transmission of molecular states changes upon lineage commitment, and in the absence of the epigenetic regulator, Polycomb. Altogether, this comprehensive study will uncover how developmentally important functional chromatin states are maintained through mitosis at the single-cell level.
2021 -
Cross Disciplinary Fellowships - CDF

Interdependence of transport and gene regulation during dormancy and growth in axillary buds

PELLETIER James (USA)

Department of Systems Biology - National Centre for Biotechnology / CSIC - Madrid - SPAIN

ARES Saúl (Host supervisor)

Shoot branching in plants integrates a wide range of developmental and environmental cues. During shoot branching, axillary buds transition from dormancy to growth, regulated by signaling factors such as hormones and nutrients, which are produced, transported, and consumed in different ways across the plant. In many species, the highly conserved transcription factor BRANCHED1 (BRC1) maintains axillary buds in a dormant state. The hormone strigolactone (SL) increases BRC1 activity and promotes bud dormancy, and sucrose decreases BRC1 activity and releases bud dormancy, but their relative contributions remain unclear. To clarify mutual dependence of transport and gene regulation during shoot branching, I will determine: (1) how BRC1 activity and axillary bud dormancy depend on transport of SL, sucrose, and other signaling factors, and (2) whether transport of signaling factors into/out of axillary buds depends on plasmodesmata (PD) constituents and aquaporins regulated by BRC1. I will develop a new microfabricated device to enable dynamic buffer control, while live confocal imaging axillary bud activity and growth. I will image fluorescent reporters in existing and new Arabidopsis lines, and I will develop mathematical models integrating transport and gene regulation, to describe and predict dormancy-to-growth transitions in isolated and interacting axillary buds. Few models of plant development have integrated transport mechanics and gene regulation in this way, so this work will have more general implications for plant development.

2021 -
Grant Awardees - Program

Feathers as structures and sensors: understanding mechanosensing in bird flight

PERKEL David (USA)

Dept. of Biology & Otolaryngology - University of Washington - Seattle - USA

WINDSOR Shane (NEW ZEALAND)

Dept. of Aerospace Engineering - University of Bristol - Bristol - UK

WOOLLEY Sarah (USA)

Dept. of Biology - McGill University - Montreal - CANADA

Birds are extremely agile and robust flyers, able to cope with challenging gusty wind conditions and perform remarkable aerial manoeuvres. To do so, birds take advantage of the flexibility of their feathers, which vibrate as a function of airflow, stimulating the mechanosensory neurons in the skin, to provide information about the airflow over the wings. We aim to explore this complex sensorimotor loop, first to identify what aerodynamic information is available to birds to help control their flight and understand how birds’ wings can act both as aerodynamic surfaces and as a distributed airflow sensing array and then to understand how this aerodynamic information is encoded in the nervous system. Although airflow sensing is thought to be critical for efficient and agile flight, almost nothing is known about how changes in airflow translate to feather movement and subsequent neural signaling. Thus, this work addresses a broad biological question about sensory encoding of aerodynamic information. This proposal represents an integrated, international collaboration to explore this question across multiple levels of organization, from the movements of feathers to neural activity during perturbed flight manoeuvres. Dr Windsor (University of Bristol, UK) is an expert in using computational image analysis to study animal dynamics and his team will use techniques from aerospace engineering to look at the aerodynamic and vibrational properties of feathered wings, including measurements of the wing motions of behaving birds. Dr Perkel (University of Washington, Seattle, USA), an expert in songbird neuroscience, will investigate the physiological mechanisms underlying the encoding of this mechanosensory information by the nervous system. His lab will record electrical signals from single neurons in the wing nerve and spinal cord of zebra finches and trace their neural pathways. Dr Woolley (McGill University, Montreal, Canada) is an expert in behaviour and neurophysiology. Her lab will map the regions of the brain responding to airflow stimuli based on insights gained from Dr Windsor’s and Dr Perkel’s groups and then measure neural responses in flying birds. By combining approaches from aerospace engineering and neuroscience we aim to understand the functional properties of wing mechanosensing that allow birds to “feel” their way through the air.
2021 -
Long-Term Fellowships - LTF

Deciphering how transcription factors modulate transcriptional bursting through enhancers

PIJUAN-SALA Blanca (SPAIN)

Genome Biology Unit - European Molecular Biology Laboratory - Heidelberg - GERMANY

FURLONG Eileen (Host supervisor)
CROCKER Justin (Host supervisor)
Gene regulation is fundamental to almost all biological processes and is the critical driving force for the generation of the diversity of cell types that make up a multicellular organism. Yet, we still do not fully understand how gene expression is regulated and modulated with changing cellular contexts. Gene transcription occurs in a discontinuous manner, where bursts of RNA production are interspersed by periods of gene inactivity. As the major regulators of the initiation of transcription, enhancers have been reported to modulate transcriptional bursting. However, how this is achieved remains largely unexplored. Here, I will investigate how enhancers influence transcriptional bursting by finely tuning the nuclear concentrations of specific enhancer-binding transcription factors (TFs) in a very precise and dynamic manner. To manipulate TF levels, I will exploit an optogenetic system recently developed by the Furlong lab, which will allow me to address this question at an unprecedented quantitative and temporal resolution for the first time in a living embryo. The functional impact of manipulating TF concentration on bursting will be quantified at two levels using state-of-the-art approaches. First, globally, using a spatial single-cell and single-molecule genomics method (intronic seqFISH+) to identify general regulatory principles. Second, dynamically, using live imaging and the MS2 and PP7 systems to dissect how burst frequency, duration and intensity are mediated by enhancers. Together, these findings will advance our understanding of gene regulation by providing new insights into the kinetics, regulation and general robustness of transcriptional bursting.
2021 -
Long-Term Fellowships - LTF

Cracking the AMPylation code in neurodevelopment

PRAVATA Veronica (ITALY)

Department of Developmental Neurobiology - Max Planck Institute of Psychiatry - Munich - GERMANY

CAPPELLO Silvia (Host supervisor)
Protein post-translational modification (PTM) is a sophisticated form of cellular information processing, essential for the emergence of organismal complexity, such as the evolutionary expansion of the cerebral cortex. Nonetheless, it is unclear how PTMs shape brain development and understanding the interconnections between these two highly complex mechanisms may open a ground-breaking avenue for tackling neurological disorders. The host lab demonstrated that protein AMPylation and the ER-specific AMPylator FICD are enriched in the neuronal niche and that FICD-mediated protein AMPylation is critical to neuronal differentiation. However, a set of the identified AMPylated proteins in neurons is enriched in proteins with mitochondrial localization, hinting that the mitochondrial-specific AMPylator SelO has an important role in neuronal mediated AMPylation and plays a critical role in neuronal metabolism and metabolic disorders. I plan to elucidate the role of the uncharacterized mitochondrial SelO using state of the art proteomic approaches in human cerebral organoids and decipher the SelO-Dependent AMPylome. I will dissect the role of SelO-dependent AMPylation in neuronal development, using a novel live imaging technique to track AMPylated proteins in mouse cortical development and human cerebral organoids. In addition, I will investigate the role of SelO in mitochondrial and cellular metabolism, using the candidates identified in the SelO-dependent AMPylome. Overall, I aim to elucidate the role of protein AMPylation in the metabolic regulation of neurogenesis, and its importance in Mitochondrial Disease and Autism Spectrum Disorders.