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2021 -
Long-Term Fellowships - LTF

Deciphering how transcription factors modulate transcriptional bursting through enhancers


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

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


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.
2021 -
Long-Term Fellowships - LTF

Mechanisms and consequences of inflammation-induced changes to skin epithelial stem cell niches


Grossman School of Medicine - New York University - New York - USA

NAIK Shruti (Host supervisor)
The skin epithelium forms a primary barrier against inflammation-inducing environmental agents and is maintained by the epithelial stem and progenitor cells (EpSCs). Stem and progenitor-cells (SCs) adapt to various conditions via crosstalk with their local microenvironment or "niche". The EpSC niche is comprised of fibroblast, neuronal, immune, and other cells that provide context-specific signals to direct SC function. However, how the EpSC niche is affected by inflammation is poorly understood. In addition to actively participating in inflammation, EpSCs also retain a memory of inflammation long thereafter, which enables more rapid responses to subsequent assaults. However, the contribution of niche factors to maintaining EpSC memory is entirely unknown. To address this knowledge gap, I propose to systematically chart the cellular constituents of the EpSC niche before, during, and after acute inflammation. Armed with this high-resolution map of the EpSC niche, I will then perform functional studies to identify niche factors that control EpSC inflammatory function and memory. Understanding inflammation-induced niche rewiring and identifying the key inflammatory niche regulators of EpSCs may illuminate mechanisms of inflammatory epithelial pathologies such as psoriasis, chronic non-healing wounds, and cancers that are rooted in SC dysfunction.
2021 -
Long-Term Fellowships - LTF

The evolution of neophobia: comparative neurophysiology of deer mice in the wild


Deparment of Organismic and Evolutionary Biology - Harvard University - Cambridge - USA

HOEKSTRA Hopi (Host supervisor)
The world around us is constantly changing – new elements appear all the time. How does the brain decide what novel things to explore? Animals exist in a constant push and pull between being adventurous and conservative. My objective is to understand how the brain controls the behavioral response to novel stimuli under naturalistic settings, and how those brain functions have been modified by evolution and ecology. During my fellowship I will approach the neurobiology of novelty from an interdisciplinary perspective that merges the evolution of behavior with its neurophysiology. I chose an ideal model system to study comparative neurophysiology: the deer mouse (genus Peromyscus). Deer mice are the most abundant mammal in North America (comprised of >50 species). Different Peromyscus species have evolved distinct behavioral repertoires. I will combine evolution and ecology with novel tools such as fiber photometry and wireless electrophysiological recording to understand the computations performed in the deer mouse brain under ethological conditions in response to novel stimuli. Specifically, I will study the brain of a variety of Peromyscus species with distinct behaviors under different novelty challenges. Overall, I will focus my research program on testing three general hypotheses: (i) different species or populations of Peromyscus will present differential response to novel objects, and (ii) dopaminergic neurons projecting to the tail of the striatum, controlling novelty responses behave differently in these species (iii) dopaminergic neurons projecting to the tail of the striatum shape neophobic behaviors in the wild.
2021 -
Long-Term Fellowships - LTF

Quantitative imaging of transcription factor dynamics during zebrafish development


Bridge Institute - University of Southern California - Los Angeles - USA

FRASER Scott E. (Host supervisor)
Gene regulatory networks (GRNs) represent the wiring diagrams of cells and can be envisioned as the blueprint for organism development. Transient interactions of transcription factors (TFs) and DNA as well as chromatin structure fine tune gene expression and allow cells with the same genome to give rise to a myriad of cell types and tissues. My overall-goal is to elucidate this fundamental process live and investigate, how exactly transient interactions, dynamics, and variations in absolute concentrations of TFs on the molecular level shape GRNs, impact on vertebrate embryo development, and can be used to infer cellular identity. Our current understanding of gene regulation arises mostly from static measurements employing sequencing technologies and in situ hybridisation approaches. However, extracting quantitative clues such as TF concentrations and their changes over time is very challenging yet crucial to shed light on the organising principles. I propose to use quantitative imaging, fluorescence fluctuation spectroscopy (FFS), and endogenous labelling of TFs to measure absolute, native concentrations and interaction dynamics directly during live zebrafish development. Using these readouts as a new handle on cellular heterogeneity, I will elucidate how specific TFs regulate hindbrain establishment and by employing engineered TFs as reporters for DNA accessibility, how overall chromatin organisation evolves in different developmental contexts. Together with the design of an open-source microscopy-spectroscopy platform tailored for in vivo FFS, this project will result in previously unattainable, quantitative insights into vertebrate embryogenesis.
2021 -
Long-Term Fellowships - LTF

ERK-mediated symmetry breaking in intestinal organoid formation


Department of Quantitative Biology - Friedrich Miescher Institute for Biomedical Research - Basel - SWITZERLAND

LIBERALI Prisca (Host supervisor)
Symmetry breaking is a process during which a homogeneous system adopts asymmetry and is fundamental during initial cell fate determination in early development and regeneration. Single-cell interactions and information exchange with the environment allows for such large-scale coordinated behaviors. Identifying mechanisms driving symmetry breaking is not trivial due to frequent nonlinear relationships between the system’s lower- and higher-order dynamics. Employing approaches from cell-, systems- and biophysical fields, I will study symmetry breaking in intestinal organoids. In a uniform growth-promoting environment, only a subset of intestinal stem cells differentiates into secretory cells. Recent evidence implicates an upstream regulatory pathway of extracellular signal-regulated kinase (ERK) in contributing to proper patterning of the stem cell niche. The proposed research aims at understanding whether and how ERK mediates symmetry breaking during intestinal organoid formation. To address this fundamental question, I will: 1) analyze the spatiotemporal-specific role of ERK signaling during symmetry breaking, 2) identify ERK-mediated tissue-level coordination focusing on biochemical and mechanical regulation, 3) determine how single-cell interactions are integrated into large-scale collective behaviors using theoretical modeling and optogenetics. This research project will determine the spatiotemporal-specific role of ERK during symmetry breaking with unprecedented multiscale resolution and provide key insights into the emergence of complexity and collective behavior fundamental to processes such as mammalian development, cancer invasion and wound healing.
2021 -
Long-Term Fellowships - LTF

Role of stress-induced modulation of B cell function in cardiovascular disease


- Icahn School of Medicine at Mount Sinai - New York - USA

SWIRSKI Filip (Host supervisor)
Cardiovascular disease (CVD) is the leading cause of global morbidity and mortality. While psychological stress is a known cardiovascular risk factor, the mechanism by which the brain translates stress into CVD is poorly understood. The underlying cause of CVD is a chronic inflammatory disease called atherosclerosis, the progression and exacerbation of which have been strongly associated with the immune system, including B cells. B cells perform many functions including production of antibodies that provide immunity against disease and cytokines that modulate leukocyte function. However, it remains unknown whether B cells mediate the effects of stress on CVD. Recent studies from the host lab show that stress profoundly affects the number and distribution of B cells in the body. This occurs via a mechanism dependent on the activation of the hypothalamic-pituitary-adrenal axis. In this proposal, I will test the hypothesis that stress aggravates atherosclerosis by modulating B cell function. To recapitulate stress, I will employ a combination of optogenetic and chemogenetic approaches available in the host lab to locally activate specific regions in the brain and characterize the subsequent impact on the phenotype and functional diversity of B cells. I will then identify the B cell-specific mechanisms that mediate the effects of stress on the progression of CVD. These studies will not only delineate potential therapeutic targets for immunomodulation of B cells in prevention and treatment of atherosclerotic CVD, but also provide a direct mechanistic link between stress and chronic inflammation, a general concept with implications beyond atherosclerosis.
2021 -
Long-Term Fellowships - LTF

The mechanics of cephalopod remarkable feeding system: how to bite without a joint


Department of Mechanical Engineering - University College London - London - UK

MOAZEN Mehran (Host supervisor)
With their multiple arms, three hearts, suckered tentacles, camera eyes, and fast colour-changing skin, cephalopods seem to come from an imaginary world. These iconic invertebrates play a major role in balancing the entire marine ecosystem, yet the 4 million metric tons caught annually have led to their global decrease. Cephalopod diet and feeding systems remain enigmatic. They have a ‘beak’ composed of two jaws with no direct contact, a radula, and specialised masticatory muscles. Unravelling the secrets of their feeding system can inform us about their diet and potentially have huge global impact by aiding their survival. In this project, I will bring together for the first-time expertise in cephalopod biology and biomechanics to quantitatively characterize the anatomy and function of the feeding system in different species representing all cephalopod families. I will use a range of techniques based on material characterization and computational modelling to test 4 hypotheses. I will investigate the (1) material content and mechanical properties of the jaws and correlate these with their bite force and diet; (2) shape and surface properties of cephalopod jaws and its potential correlation with their diet; (3) muscular jaw articulation of cephalopods and the mechanisms that control its motion considering a range of diet; (4) impact of overall jaw and muscular joint morphology on the level of mechanical strain across each component. A major part of cephalopod biology will be unravelled in this project, providing new foundations for cephalopod conservation and other areas such as bioinspired soft robotics.
2021 -
Long-Term Fellowships - LTF

The mechanistic role of metabolism during germ layer specification and symmetry breaking


Tissue Biology and Disease Modelling - European Molecular Biology Laboratory - Barcelona - SPAIN

TRIVEDI Vikas (Host supervisor)
The role of metabolism during developmental processes remains largely unexplored due to challenges in measuring spatiotemporal dynamics of metabolic activities. In the mammalian post-implantation embryo, pluripotent cells differentiate into three germ layers, the ectoderm, mesoderm and endoderm that undergo specific morphogenetic movements during a process known as gastrulation. While it is known that metabolites influence cell fate by modifying the epigenetic and transcriptional states, the question, whether metabolism plays a functional role in germ layer specification, has not been addressed in an in vivo context. The two main aims of the proposed project are to characterize the metabolic profiles that accompany the emergence of germ layers and their possible function during germ layer segregation i.e. symmetry breaking that establishes the primary body axis. To accomplish both aims, I will use gastruloids, aggregates of embryonic stem cells that recapitulate hallmarks of gastrulation, as a model system. The gastruloid system will allow me to combine metabolic measurements, live imaging of biosensors and metabolic state reconstruction, to uncover emerging differences in metabolism among cells of the different germ layers. Further specific manipulations with inhibitors and optogenetic tools will test if the activity of certain metabolic pathways regulates cell fate decisions and coordinates tissue scale cell movements and thus probe possible molecular mechanisms. The findings of this project will reveal fundamental mechanisms underlying the interplay between metabolism and cell fate determination and thereby change our view of how gastrulation is robustly regulated.
2021 -
Long-Term Fellowships - LTF

Saving the reef: identifying molecular and environmental factors underlying spawning in A.millepora


Arc Centre of Excellence for Coral Reef Studies - James Cook University - Townsville - AUSTRALIA

MILLER David J. (Host supervisor)
Broadcast spawning is a method of reproduction used by many species of coral, where the corals release their gametes in a perfectly timed, synchronous manner to maximise fertilisation. The timing and molecular mechanism behind this extraordinary event are not understood. Coral bleaching and the death of reefs is something that is now firmly anchored in the public consciousness. However, another threat is looming for coral, the asynchrony of spawning. This marginalised ecosystem now faces an even bigger threat, the possibility of not being able to reproduce, spelling disaster not just for marine life, but also for the communities that depend on them. An understanding of this asynchrony is key and I have therefore designed a research plan which examines the molecular mechanisms behind the spawning event. In particular, I aim to study the light biology of coral, as they use multiple light stimuli, including moonlight, to regulate reproduction. To this day, we do not know what photopigments corals employ, where these are located and whether the algal symbiont is key in initiating different spawning steps. Moonlight is the critical signal, however, the full moon is present every 29 days, so another gating mechanism must exist. I aim to find out exactly what this is by varying different parameters in a lab setting. Using temporal differential gene expression analysis around this critical moonlight signal will provide a basis for understanding the key cellular responses driving spawning. Pioneering a deep understanding of reproductive asynchrony will allow the implementation of improved conservation measures and help save the world’s reefs from destruction.
2021 -
Long-Term Fellowships - LTF

Neuronal mechanisms underlying group social interactions in bats


Department of Bioengineering - University of California - Berkeley - USA

YARTSEV Michael (Host supervisor)
The group setting forms the basis for most social interactions. However, despite the importance of group social behavior in almost every aspect of animal’s lives, very little is known about its neuronal substrates. This can be attributed to challenges associated with reductionist approaches to capture the complexity of group social interactions. Thus, a paradigm shift is necessary. Specifically, we identify these major gaps where most studies have: (1)focused on one brain at a time, (2)often did not consider individual differences and (3)neglected the long-term dynamics of group social behavior, especially in the natural context. To overcome these gaps, I propose an approach that leverages the rich social interactions in groups of bats, a new animal model for group social interactions in neuroscience. Utilizing cutting-edge methodologies that enable simultaneous wireless recording and manipulating of neural activity across the brains of group members, I will study the neural mechanisms of group social interactions as these naturally unfold. I will begin by focusing on two core aspects of group social interaction and their manifestation in the frontal cortex of socializing bats: (1)neuronal representations of individual’s identity as related to social vocal communication, (2)interbrain coupling across group members. Thus, I will study the relationship between group social and neural dynamics extending from the single neuron level in the individual brain to the relationship in neural dynamics across the brains of group members. Combined, this project will allow, for the first time, a unique mapping of the group social network onto the neuronal network of its members.
2021 -
Long-Term Fellowships - LTF

Revealing autolytic mechanisms of sieve element differentiation by improved phloem induction system


Sainsbury Laboratory - University of Cambridge - Cambridge - UK

HELARIUTTA Yrjö (Host supervisor)
In order to gain something, sometimes you have to lose something. This is true in our lives, and it is also true for cells to gain special functions. The individual component of the phloem sieve tube, the sieve element (SE), loses the cytoplasm, organelles, and even part of the cell wall to be able to transport photosynthetic products and signaling molecules over long distance. However, the molecular mechanisms behind these dramatic changes have been shrouded in mystery for more than 60 years since the discovery. The main reason for this is due to the small size of SEs and their deep location in the tissue, which makes them extremely difficult to observe with confocal live imaging. In this proposal, I aim to reveal the autolytic mechanisms of SEs by establishing a novel SE induction system that overcomes such technical hurdles. This research provides new insights into the coupling between autolysis and cell specialization. It also has the potential to expand the field of plant science, as plant development have rarely been studied in terms of degradation control.
2021 -
Long-Term Fellowships - LTF

Programmable protease circuits to control vaccine immunogenicity


Department of Chemical Engineering - Stanford University - Stanford - USA

GAO Xiaojing (Host supervisor)
The development of vaccines to prevent morbidities from infectious diseases remains one of medicine’s greatest achievements. However, many successful vaccines have been developed empirically and vaccine efficacy is highly variable. Rationally differentiating immune cells to specific fates such as memory T cells to improve long-term vaccine efficacy is limited by current methods for controlling differentiation, in part due to inadequate quantitative and temporal control of cytokines. In this work, we propose to overcome these limitations by using engineered cells to function as programmable tools that can respond to combinatorial environmental inputs and produce controlled responses for interrogating basic biology of memory formation and its application in vaccination in an entirely human-derived system. I propose to construct a generalized platform (CHOMP-sec) to detect and secrete proteins using synthetic protein circuits. This platform will be used to systematically scan the effect of IL-2 expression and dynamics on driving the differentiation of memory CD8+ T cells using patient-derived tonsil organoids. The proposed work will provide the field of Immunology with tools to quantitatively control cytokine secretion and a new framework for exploring immune cell differentiation for additional applications, such as inducing tolerance by biasing regulatory T cell responses to engineered tissues.
2021 -
Long-Term Fellowships - LTF

Algorithms and circuit mechanisms underlying distance estimation in larval zebrafish


Department of Molecular and Cellular Biology - Harvard University - Cambridge - USA

ENGERT Florian (Host supervisor)
All species need to navigate, forage, and interact with other animals in a constantly changing threedimensional world. For such behaviors, vision is one of the most important senses as it allows animals to map their immediate surroundings from a distance which in turn helps coordinating ongoing and future motor actions. To construct such a map, the visual system uses a wide variety of depth cues such as object size, binocular disparity, texture, accomodation, shading, perspective, motion parallax, and occlusions. However, despite extensive research into the function of visual systems, currently, it still remains unclear what the exact perceptual algorithms and circuit mechanisms underlying depth perception are. Therefore, I propose to investigate how larval zebrafish process depth information and use such cues during hunting behavior. Given its small size, genetic tractability, optically accessible brain, and rapid development of visually driven behaviors, the larval zebrafish is an ideal vertebrate model system to tackle these questions. Starting at 5 days post fertilization, larvae visually hunt small protists. At the start of a hunting sequence, they almost invariably select the closest prey, which suggests that they posses a way of visually estimating distance. In order to investigate how larvae perform this feat, I plan to design and build a novel virtual reality system than can provide both monocular and binocular depth cues to a freely swimming or restrained zebrafish larva. Using this VR system, I then aim to determine which depth cues are utilized and investigate their neuronal representation using whole-brain two-photon imaging.
2021 -
Long-Term Fellowships - LTF

Mechanisms of 5´UTR-mediated translational dysregulation in cancer


Institute for Regenerative Medicine - University of Zurich - Zurich - SWITZERLAND

SENDÖL Ataman (Host supervisor)
The dysregulation of protein synthesis in favor of oncogenic proteins is a hallmark of cancer. Recent discoveries revealed that translation of upstream open reading frames (uORFs) within 5´ untranslated regions (5´UTRs) of oncogenic messenger RNAs (mRNAs) contributes substantially to increased oncogene synthesis during cancer initiation. Although we begin to understand the molecular mechanisms underlying the specific programs of protein synthesis, we lack a general picture of the order of events that lead to the remodeled protein synthesis in cancer. Here, I propose to develop, validate and apply a split-fluorescent uORF/mainORF (mORF) reporter system that recapitulates preferential oncogene translation in a squamous cell carcinoma (SCC) model. I aim at developing and characterizing this reporter system in order to record for the first time the translational remodeling in an in vivo mouse cancer model during transition from healthy tissue to different stages of tumor formation. In addition, this approach will enable me to screen for factors involved in the induction of oncogenic drivers by 5´UTR-associated mechanisms. Finally, I will also reveal the molecular mechanisms by which the newly identified factors drive translational reprogramming in cancer. My findings will substantially contribute to our understanding of protein synthesis pathways during health and disease and provide a foundation for the development of novel cancer therapies.
2021 -
Long-Term Fellowships - LTF

S1DZ neuronal representations during social behavior and the effect of cytokines on this activity


Department of Brain and Cognitive Sciences - Massachusetts Institute of Technology - Cambridge - USA

CHOI Gloria B. (Host supervisor)
Maternal immune activation (MIA) in pregnant mice has been shown to induce phenotypes resembling those of Autism spectrum disorder (ASD) in offspring, among those are deficiencies in social interaction. A recent study showed social behavior deficits can be temporarily rescued by eliciting an inflammatory response. Specifically, it was shown that administration of lipopolysaccharide (LPS) induces interleukin-17a (IL-17a) or direct administration of IL-17a into primary somatosensory cortex dysgranular zone (S1DZ), promoted sociability in these mice. These results raise the following questions: (a) what is the role of S1DZ in sociability? And (b) how does IL-17a affect the neuronal activity in this brain area that rescues social behavior deficits? In my postdoctoral studies I plan to answer these questions by recording neuronal activity in S1DZ in freely moving MIA-affected and control mice during social interaction and characterize the neuronal representations in this brain area. Moreover, by administrating IL-17a I will study how this cytokine act as a neuromodulator affecting the neuronal activity in S1DZ. Identifying the role of S1DZ in social behavior and the underlying mechanisms increasing sociability that are prompt by the presence of IL-17a, will pave the way to design potential treatments for behavioral abnormalities manifested in ASD phenotypes.
2021 -
Long-Term Fellowships - LTF

Artificial intelligence-driven identification of in vivo RNA structure motifs in RNA degradation


Department of Cell and Developmental Biology - John Innes Centre - Norwich - UK

DING Yiliang (Host supervisor)
RNA structure plays a crucial role in regulating gene expressions such as translation and RNA degradation. Considering the advance of high-throughput sequencing, researchers are currently able to access both in vivo RNA structures and RNA degradation information over tens of thousands of RNAs in one single experiment. However, it is still unclear which RNA structure feature/motif is generally responsive to RNA degradation in living cells. It is challenging for traditional analysis methods to process the emerging " big data" of RNA structure in vivo, and they are not able to assess the complexity of RNA structure features for the whole RNA, which is over thousands of nucleotides long on average. In this project, I aim to develop novel artificial intelligence (AI) frameworks incorporating deep learning and omics approaches to determine in vivo functional RNA structure motifs in RNA degradation. By integrated multi-omics data, I will construct deep learning models to establish the relationship between RNA structure and RNA degradation and consequently extract the potential RNA motifs. The combination of dry-bench and wet-bench methods will allow me to develop a prediction-validation working scheme to solve this multidisciplinary problem. Based on the identified functional RNA structure motifs, I will also establish corresponding web servers for the community to predict/design the RNA structure motifs for the RNA of interest. The proposed research will make major advances in our fundamental understanding of the RNA structure functionality in RNA degradation in living cells and the AI framework will enable further applications to the complex genomics dataset.
2021 -
Long-Term Fellowships - LTF

Elucidating the role of nuclear envelope budding as a non-canonical route for exporting large-RNPs


Department of Molecular, Cellular and Developmental Biology - University of Colorado - Boulder - USA

VOELTZ Gia (Host supervisor)
For decades, the nuclear pore complex (NPC) has been considered the sole gateway between the nucleus and the cytoplasm, allowing transport of molecules across the nuclear envelope (NE). However, in recent years NE budding emerged as a non-canonical alternative route for nuclear export of viral nucleocapsids, as well as for large ribonucleoparticles (RNPs). Yet, very little is known about the significance of this unconventional export pathway. The project proposed here aims to elucidate the role of NE budding as a non-canonical route for exporting large-RNPs. The strategy I propose is to track and perturb NE budding transport of large-RNPs. In particular, I will study: (I) the relationship between NE budding and NPC canonical export pathway; (II) its potential involvement in nuclear quality control; and (III) I will test the hypothesis that lamin and Torsin protein families participate in NE budding of large cellular complexes. To follow RNP trafficking and image NE budding events, I will apply state-of-art RNA live-imaging techniques and use a combination of cryo-electron microscopy and tomography (cryo-EMT) and high-resolution live-cell microscopy. Moreover, I will apply biotin proximity ligation assay (BioID) to identify novel RNA and protein cargos transported through NE budding in a Torsin-dependent manner. The results stemming from the work proposed here will represent a significant step towards understanding NE dynamics, and may shift the current dogma of nuclear export.
2021 -
Grant Awardees - Program Grants

Memory – from material to mind


Tactile Perception and Learning Lab - International School for Advanced Studies (SISSA) - Trieste - ITALY

KEIM Nathan (USA)

Dept. of Physics - Pennsylvania State University - University Park - USA


Faculty of Medicine and Network Biology Research Laboratories - Technion - Israeli Institute of Technology - Haifa - ISRAEL

The brain’s capacity to store and retrieve information is the target of enormous research efforts. Seemingly unrelated research in physics has begun to focus on information storage and retrieval in non-living systems. For instance, a crumpled nickel-titanium wire spontaneously reconfigures into its remembered shape – a paperclip – upon heating. Our proposal posits that the memory dynamics being discovered in non-living systems are less remote from brain memory than might be supposed. Through our experimental neuroscience expertise (DIAMOND), we will train rats in perceptual memory behaviors. To uncover fundamental rules that extend beyond a single paradigm, we will use one stimulus set as the external drive from which the brain generates multiple distinct percepts; furthermore, we will train rats to act upon these percepts in a diverse library of tasks. Through our soft matter physics expertise (KEIM), we will chart out a general framework for memory storage and retrieval aimed at replicating key rat findings, such as the interaction between short-term and longer-term memories. Materials that extract and store information, such as driven suspensions, can be arranged in a flexibly interacting network to serve as a physical model of brain networks. Our computational neural networks expertise (BARAK) will act as the bridge. In a feedback loop within the project, BARAK will characterize materials networks in a language that can be applied to experimental neuroscience. By converting materials network properties into biological mechanisms, such as persistent firing patterns, BARAK will provide DIAMOND with quantitative predictions for the neuronal population states across a network of cortical regions (analogous to the network of materials). Removal of a single module from the materials network might be analogous to optogenetic suppression of a single cortical region; the team, together, will interpret parallel experiments of this sort. While not neglecting what makes the brain qualitatively different from an inanimate material, our identification of common motifs between material and mind engenders a new approach that envisions behavior as the task-dependent configuration of a repertoire of fundamental memory properties.
2021 -
Grant Awardees - Program Grants

Adaptation of photosynthetic membranes to environmental change


Department of Chemistry - Southern Methodist University - Dallas - USA

ENGEL Benjamin (USA)

Helmholtz Pioneer Campus - Helmholtz Zentrum Munich - Neuherberg - GERMANY


Dept. of Physics and Astronomy/Biophysics of Photosynthesis - Vrije Universiteit Amsterdam - Amsterdam - NETHERLANDS

Photosynthetic organisms convert sunlight into biochemical energy, thereby sustaining most of the life on Earth. Changing light conditions present a fundamental challenge for these organisms, which must find a balance between increasing productivity and avoiding damage caused by overexciting the photosystem protein complexes embedded within their thylakoid membranes. Regulatory mechanisms such as state transitions and non-photochemical quenching are proposed to involve major remodeling of the thylakoid membranes and their embedded light-harvesting protein complexes. However, despite decades of intense research activity providing indirect supporting evidence, the molecular adaptation of thylakoids has never been directly observed, and there remains a disconnect between the relatively slow membrane remodeling steps and the ultrafast process of light harvesting. In our newly-formed team, we have assembled a novel combination of multidisciplinary expertise and innovative technology aimed at breaking through this longstanding barrier in the field.