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Funding
Funding
HFSP supports novel, innovative and interdisciplinary basic research focused on the complex mechanisms of living organisms. A clear emphasis is placed on novel collaborations that bring biologists together to focus on problems at the frontier of the life sciences.
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Awardees
Awardees
In this section you find information about the awardees in the HFSP scientific programs. This includes a searchable database of HFSP awardees, information on the HFSP Nakasone Award and other achievements by HFSP awardees.
- News & Impact
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Events
Events
HFSP promotes and participates in several events every year. We are committed to bringing together the scientific community and forging new opportunities to network and have scientific discussions that help to create bridges and partnerships for the future of frontier science.
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About
About
The Human Frontier Science Program is a program of funding for frontier research in the life sciences. It is implemented by the International Human Frontier Science Program Organization (HFSPO) with its office in Strasbourg. Here you can find all you need to know about the HFSPO.
Awardees
2022
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Long-Term Fellowships - LTF
The cellular and developmental genetic mechanisms underlying germline response to climate change
RAJAKUMAR Arjuna (.)
. - Whitehead Institute for Biomedical Research - Cambridge - United States
LEHMANN Ruth (Host supervisor)
Fertility is declining globally for a range of animals including insects, fish, and mammals. Rising temperatures due to climate change are expected to worsen this problem because temperature is known to influence key biological processes including immunity and cellular physiology, and abnormal temperature levels can elicit a maladaptive response. While organisms have evolved the capacity to respond to fluctuating environments in a constant and predictable way, a capacity known as canalization, previous work indicates that the germline is temperature sensitive, where high temperatures induce sterility. We propose to use Drosophila melanogaster as a model to understand the mechanistic basis of temperature-induced sterility through the following aims: 1) Combining developmental genetics with super-resolution microscopy, we will test how temperature affects germplasm assembly and whether intrinsic disordered domains, characteristic of germ granule proteins, are involved in temperature sensing. 2) Using hybrid dysgenesis, a system that generates sterile progeny and is exacerbated by high temperatures, we will test whether piRNA pathway control and transposable element activity change across a temperature gradient. 3) Using Drosophilid populations adapted to high temperatures, we will test if mitochondria purifying selection within the germline is temperature-optimized and whether mitochondria transplantation from adapted to non-adapted individuals can modulate temperature-induced sterility. Altogether this work will further our understanding of the cellular and molecular mechanisms underlying the germline response to temperature and how this may be impacted by climate change.
2022
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Long-Term Fellowships - LTF
Revealing the control of epithelial mechanics during wound healing using in vivo force manipulation
ROGALLA Svana (.)
. - Instituto Biofisika, Basque Centre for Biophysics (UPV/EHU, CSIC) - Leioa - SPAIN
SOLON Jerome (Host supervisor)
Wound healing is a dynamic process in which a living organism replaces lost or damaged tissue based on molecular, hormonal and cellular responses. Understanding the mechanics behind the cellular responses during wound healing processes is a key question in biology and biomedicine, however, the contribution of tissue mechanics (setting tissue deformation upon forces) to wound healing in live animals remains poorly understood. In this project, I will use live Drosophila melanogaster embryos as a model system to reveal how changes in epithelial mechanics are controlled during wound repair. Combining Drosophila genetics with laser dissection, and a novel procedure allowing the application of controlled forces on a single magnetic particle embedded within the tissue in vivo, I will measure the changes in epithelial mechanics within the wounded tissue and link these to specific wound healing regulatory signals. The project will comprise three consecutive stages: 1) I will measure changes in mechanical forces during the different phases of wound healing and correlate them with activation of biochemical signals, such as Hippo and JnK pathways. 2) Based on these measurements and in collaboration with theoretical physicists, I will create a biophysical model of wound healing processes. 3) I will investigate the effect of ectopic forces on the kinetics of wound healing and on cell response, particularly focusing on potential modulation in gene activity by mechanical perturbation. Altogether, these experiments will allow to reveal the control of wound healing in vivo encompassing mechanical and biochemical signals and the resulting changes in epithelial mechanics and cellular forces.
2022
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Long-Term Fellowships - LTF
Deciphering the nature of genomic conflict using locus-specific chromatin perturbation and capture
RUDNIZKY Sergei (.)
. - Johns Hopkins University School of Medicine - Baltimore - United States
HA Taekjip (Host supervisor)
Chromatin modulates DNA accessibility and hence serves as a fundamental layer in the complex regulation of gene expression and DNA integrity. However, the role of chromatin organization in resolving a genomic conflict between two seemingly competing processes – transcription and DNA damage response (DDR) is not clear. This stems from the dynamic nature of chromatin that is transcribed and repaired in an asynchronous and position-dependent manner. Moreover, locus-specific purification of mammalian chromatin, usually found with only two copies per cell, presents a major challenge regarding the necessary assay specificity and sensitivity. To overcome these limitations, I will develop a single-molecule (SM) pulldown approach based on multi-step enrichment with CRISPR Cas9 and Cas12a, followed by Oligopaint to capture and dissect any chromatin locus of interest. Using light-activated vfCRISPR, I will introduce lesions at transcriptionally active or silent regions to induce DDR with high spatiotemporal control. Captured chromatin will be characterized by SM and super-resolution imaging regarding its composition and organization and will be used as a native substrate to access the dynamics of transcription and DNA repair factors in real-time. Coordination between transcription, DDR, and local chromatin will be examined by guiding vfCRISPR to the promoter and gene body of the heat-shock induced Hsp70 model gene. The developed method can be expanded to mouse models and can be broadly applied to genomic regions of high relevance to health and disease, providing an exciting opportunity for understanding the fundamentals of transcription and DDR in vivo at unprecedented resolution.
2022
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Long-Term Fellowships - LTF
Are endothelial cells regulated differently during limb regeneration than during development?
SAVAGE Aaron (.)
. - President & Fellows of Harvard College - Cambridge - United States
WHITED Jessica (Host supervisor)
Biological question
My question is: how is vascular regrowth regulated during limb regeneration? I aim to understand— at a precise molecular, genetic, and cellular level— how vascular regeneration is regulated in axolotls; whether by angiogenesis or novel mechanisms remains unclear.
Scientific content
This multi-disciplinary project spans developmental biology, genomics, and regenerative medicine, combining cutting-edge transcriptomic, imaging, and molecular biology practices analyze vascular regeneration in axolotl limbs.
Specific aims: 1) Generate the first axolotl vasculature map, using CRISPR knockin-generated transgenics, contrasting native vascular limb patterning to post-regeneration limb patterning; 2) Analyze regenerating vascular cells transcriptionally to elucidate key genes/pathways, using single cell RNA sequencing; 3) Perform in vitro and in vivo assays (morpholino/CRISPRi knockdown; mutagenesis, etc.) to characterize how interplay between key genes/pathways regulates how blood vessels and other tissues, such as fibroblasts interact, informing limb regeneration.
Novel transgenics will express both vascular-specific fluorescent proteins and the TVA receptor, enabling visualization of expression and spatiotemporal delivery of molecular modulators, for precise control of gene expression.
Significance
To understand limb regrowth, it is essential to understand complex interactions between different cell types during regeneration. This project will pioneer characterization of regenerating vessels, informing both wider understanding of limb regeneration and how vessels can be reactivated, generally, to expand in response to injury and disease.
2022
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Long-Term Fellowships - LTF
The ecological role of bacterial specialized metabolites in bacteria-microalgae interactions
SCHLEYER Guy (.)
. - Leibniz Institute for Natural Product Research and Infection Biology – Hans Knöll Institute (HKI) - Jena - GERMANY
HERTWECK Christian (Host supervisor)
Phytoplankton are marine photosynthetic microorganisms that thrive in the photic zones of the oceans. They form the basis of marine food-webs and greatly influence global biogeochemical cycles and the climate. Many studies highlighted the importance of microbial interactions in shaping community composition, especially bacteria-phytoplankton interactions. Over the past decade, chemical communication was found to be a key aspect in mediating these interactions, such as mutualism and pathogenicity. Although bacteria are prolific producers of specialized metabolites, also known as natural products, the involvement of such metabolites in bacteria-phytoplankton interactions has been largely overlooked. Moreover, these metabolites have been studied mostly for pharmaceutical purposes rather than for their role in nature.
This research is aimed at studying bacterial specialized metabolites and their involvement in mediating bacteria-phytoplankton interactions. To achieve this, I will study ecologically-relevant bacteria-phytoplankton systems, both mutualistic and pathogenic, mediated by chemical communication. The systems will be developed in collaboration with the Pohnert group, which has been studying numerous systems of bacteria-algae interactions. I will identify bacterial specialized metabolites that mediate these interactions using analytical chemistry tools and will further characterize their biosynthetic pathways and their cellular targets using diverse biochemical techniques. These findings will shed light on the role of specialized metabolites in governing bacteria-microalgae interactions and allow us to better understand their ecological role in nature.
2022
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Long-Term Fellowships - LTF
Using computational models to link dynamics of brain plasticity with behavioral changes over time
SCHURR Roey (.)
. - President & Fellows of Harvard College - Cambridge - United States
GERSHMAN Samuel (Host supervisor)
The ultimate goal of neuroscience is to provide a mechanistic explanation of the cognitive processes that drive human behavior. I propose to study the link between changes in one’s brain connectivity and structure and one’s behavioral changes, by integrating computational models, behavior and neuroimaging. Specifically, I will study the dynamical changes of behavioral and neuroimaging measurements to uncover the computational infrastructure of core cognitive processes.
Computational model of behavioral yield subject-specific parameters. These parameters provide a mechanistic explanation to the cognitive process and to inter-subject variability. However, no large-scale longitudinal study has approached the source of observed changes in the estimated parameters over time. Is it measurement noise or true variability in the cognitive process?
I will collect longitudinal data of behavior and neuroimaging from subjects who will perform seven behavioral tasks with established computational models. By studying the covariance of computational parameters over time, I will identify latent factors that may represent core cognitive process (e.g. working memory). I will explore the hypothesis that these latent factors reflect shared neural circuitry across tasks. In particular, I will test whether the dynamical changes in the computational phenotype are associated with functional and structural changes in specific brain networks. Finding such a link between model-based parameters and neuroimaging measurements will be a major step towards a mechanistic understanding of the computational and anatomical infrastructures that underlie core cognitive processes in the human brain.
2022
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Long-Term Fellowships - LTF
Unravelling the mechanisms of bis(monoacylglycero)phosphate synthesis and function in endolysosomes
SINGH Shubham (.)
. - Sloan Kettering Institute for Cancer Research - New York - United States
FARESE Robert (Host supervisor)
Bis(monoglycero)phosphates (BMP) are a structurally unique orphan lipids exclusively localized at endolysosomal systems in the cells. Studies suggests that BMP might play a crucial role in the endolysosomal system by regulating lysosomal hydrolase activity, cholesterol transport and budding of lysosomal intralumenal vesicles. Interestingly, BMP levels are deregulated in various neuropathological conditions characterized by defective endolysosomal system like Niemann-Pick Disease Type C, Gaucher’s disease, Fabry disease, and dementia, etc. Though BMP were discovered five decades back and studies suggest their indispensable role in the endolysosomal physiology, nothing is known about their exact function, metabolism and how their deregulated levels associate with the neurodegenerative diseases. In this proposal, I aim to identify the enzymes that synthesize and degrade BMP in mammalian cells, and exhaustively characterize their role in the endolysosomal systems. I will use chemical genetic and siRNA strategies in conjunction with lipidomics to identify the enzymes that regulate BMP levels. Using in vitro reconstitution, I will determine the function of candidate enzymes and regulators in BMP metabolism. I will use genetic manipulations targeting enzymes to selectively modulate BMP levels in the cells/rodents, and examine their role in the endolysosomal physiology especially in the neurons. Overall, the results of the proposed studies will not only help in mapping BMP metabolism in cells but will also aid in understanding of the role of BMP in the endolysosomal physiology.
2022
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Long-Term Fellowships - LTF
Enhancing receptor signaling by liquid condensate formation
SONG Daesun (.)
. - The Board of Trustees of the Leland Stanford Junior University - Redwood City - United States
LIN Michael (Host supervisor)
Transmembrane receptors activate intracellular signaling pathways mediating growth, survival, or differentiation. Liquid condensate formation by T cell receptors enhances downstream signaling, but whether condensation can generally enhance receptor function is unknown. I propose to study the ability of condensation to generally enhance receptor function using the epidermal growth factor receptor (EGFR) as a model, with the following aims:
1. Design inducible EGFR condensates. Fusions of cryptochrome 2 (CRY2) and the Fused-in-Sarcoma intrinsically disordered region (IDR) form droplets in response to blue light, while cryptochrome variants CRY2olig and GFP-CRY2high without IDR create visible accumulations of unknown liquidity. I will fuse EGFR-GFP to CRY2-IDR, CRY2olig, or CRY2high and assess liquidity of light-induced accumulations by time-lapse morphology and FRAP.
2. Compare signaling –/+ EGFR condensation. I will activate the above proteins –/+ light –/+ EGF, comparing to EGFR-GFP, while measuring amplitude and kinetics of EGFR/Akt/ERK phosphorylation, Shc-RFP recruitment, and receptor internalization. This will determine if condensation enhances signaling, and if so at what step and in what manner.
3. Determine if any observed signaling enhancement also augments function by assessing proliferation of keratinocytes expressing EGFR-EGFP or the above fusions –/+ light –/+ EGF.
This project will combine my existing expertise with liquid condensates from my Ph.D. training with the expertise of the Lin Lab at Stanford in CRY2 biochemistry and EGFR signaling to obtain insights into the role of condensation in organizing and amplifying biological signals.
2022
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Long-Term Fellowships - LTF
Functional cell atlas of neural crest cell contribution to newt development and regeneration
SUZUKI Miyuki (.)
. - California Institute of Technology - Pasadena - United States
BRONNER Marianne (Host supervisor)
During development, neural crest stem cells arise within the forming central nervous system but then migrate into and throughout the periphery where they differentiate into diverse cell types. In addition to their importance in development, neural crest cells have recently been implicated in organ regeneration (e.g. heart regeneration in adult zebrafish) raising the intriguing possibility that they may be required in multiple regenerating structures. Salamanders have the remarkable regenerative ability and represent an excellent model for exploring the role of neural crest cells in both organogenesis and organ regeneration. To identify neural crest-derived cells that potentially re-express a neural crest gene regulatory program during organ regeneration, I have established Sox10::EGFP and Cre/loxP transgenic newts, Pleurodeles waltl, that genetically label and enable visualization of Sox10-expressing cells in vivo. With this in hand, I will explore two pressing questions: 1. Do neural crest-derived cells contribute to adult limb and heart regeneration in the newt? 2. If so, what are the underlying molecular mechanisms? To address these questions, in Aim 1, I will generate an atlas of cell types formed by neural crest-derived cells using Cre/loxP technique; in Aim 2, I will evaluate the involvement of neural crest-derived cells in organogenesis and organ regeneration using in vivo cell ablation technique. Aim 3 will generate a single-cell RNA-seq transcriptome profile during the regenerative process. This comprehensive atlas of cellular fates and functions of neural crest in newts promises to deepen understanding of development and regeneration in vertebrates.
2022
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Long-Term Fellowships - LTF
Investigating the regulomic basis of major evolutionary transitions
TAYLOR Benjamin (.)
. - Purdue University - West Lafayette - United States
HARPUR Brock (Host supervisor)
The evolution of life on Earth has been extensively shaped by major transitions in biological complexity. The evolution of insect eusociality is one such transition and has occurred multiple times independently in recent evolutionary history. Unfortunately, the mechanistic basis of this transition is poorly understood. One major hypothesis proposes that eusociality is associated with substantial increases in gene regulatory complexity, but no study to date has provided a robust empirical test of this possibility. I propose to provide such a test. Using a novel meta-analytic machine learning approach, I will integrate new and existing multi-omic datasets from eusocial, subsocial, and solitary hymenopteran species to identify phylogenetically-robust signatures of the transition to eusociality. I predict that eusocial species will exhibit substantial expansions in regulatory complexity compared to related solitary taxa, in the form of increases in the proportion of the genome that is subject to alternative splicing or epigenetic regulation. Additionally, I will combine population genomic data and lab-based transgenic experiments to validate the functional role of regulatory loci, thereby corroborating the causal role of the regulome in generating complex social phenotypes. This project will integrate my experience in machine learning and gene expression analysis with expertise in alternative splicing and functional genomics provided by Dr Harpur’s group. Doing so will allow us to greatly advance our understanding of how social life evolves and diversifies by answering a fundamental biological question: how can biological complexity evolve without increases in gene content?
2022
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Long-Term Fellowships - LTF
Templated polypeptide synthesis inside a nanopore cavity
TOPARLAK Omer duhan (.)
. - University of Oxford - Oxford - United Kingdom
BAYLEY Hagan (Host supervisor)
Genetically-coded protein synthesis is the universal hallmark of cellular life, where the ribosome is the central figure, linking nucleic acids to protein catalysts. Yet, our understanding of templated polypeptide synthesis is restricted to the extant ribosome and its engineered derivatives, with its limited chemistry. In order to facilitate the design of artificial ribosomes by simplifying the complex nature of the task, we propose to study peptide bond formation and the DNA-templated polymerization of amino acids within a nanotube cavity. Recent developments in nanopore technologies have unlocked the potential of single molecule chemistry with angstrom-level precision. To this end, we will utilize phi29 DNA packaging motor nanopores, which will allow the base pairing between template DNA and aminoacylated polynucleotides as activated substrates. Inspired by non-ribosomal peptide synthesis and prebiotic reactions on the early Earth, we will explore thiol-thioester, thiol-disulfide and S-to-N acyl transfer reactions. We will make use of thioester-activated (e.g. acetyl-CoA) and aminoacylated trinucleotides as transfer RNA mimics to drive polymerization. Modified or unnatural amino acid side chains on the nanopore wall can enable otherwise uphill condensation reactions. The newly synthesized polymers will not be restricted to the inclusion of natural amino acid side chains or conventional polypeptide backbones. The synthesis will take place continuously, at a useful rate and without the need for an external fuel. The ultimate chemistry we propose will enable (bio)chemists to produce efficient protein synthesis devices that will serve as a foundation for synthetic cells.
2022
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Long-Term Fellowships - LTF
Chemical and optogenetic approaches to identify and quantify the membrane sources of autophagosomes
UEMATSU Masaaki (.)
. - Cornell University - Ithaca - United States
BASKIN Jeremy (Host supervisor)
Autophagy is one of the main systems for the degradation of intracellular components. In this dynamic process, an ad hoc membranous structure called an autophagosome is transiently created to engulf cytoplasmic cargo to be degraded. Previous studies have identified many proteins essential for autophagy. However, the membrane sources of autophagosomes are still under debate, in large part due to the lack of direct methods to measure inter-organelle lipid transport with high spatiotemporal resolution.
I propose to develop a method to locally label lipids on donor organelle membranes and detect them on the destination organelle (autophagosome) after lipid transfer. I will use a unique system, developed by my host laboratory and termed optoPLD, a light-controlled enzymatic tool that can produce labeled lipids from phosphatidylcholine (PC) on specific organelle membranes. For the labeling, I will engineer optoPLD to produce deuterated PCs on the donor membrane. For detection, I will generate a second optoPLD with an orthogonal optogenetic tool that can be activated with different wavelength of light to release the deuterated portion of PCs on the destination membrane via hydrolysis. I will measure the deuterated fraction of the released moiety to quantify the amount of transferred lipid.
Combining this method with the acute knockdown of autophagy-related proteins to accumulate autophagosomes will determine the fractional contribution of organelles to the membrane sources of autophagosomes. Beyond autophagy, I envision that this method will be applicable to investigate any inter-organelle lipid transport, providing a much-needed tool to understand lipid homeostasis.
2022
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Long-Term Fellowships - LTF
Haemogenic gastruloids: a novel approach to generate and study blood stem cells in vitro
VAN DEN BRINK Susanne carina (.)
. - Institut Hospital del Mar d'Investigacions Mèdiques (Hospital del Mar Medical Research Institute, IMIM) - Barcelona - SPAIN
BIGAS Anna (Host supervisor)
Bone marrow haematopoietic stem cell (HSC) transplants are life-saving treatments in a plethora of haematological and non-haematological malignancies. The availability of HSC transplants is limited, and there has been little success in producing or expanding HSCs in vitro. Rare instances of in vitro production of HSCs are of low efficiency and require ectopic expression of multiple genes, limiting their clinical applicability. During embryonic development, HSCs are formed in a specific niche which is key to HSC production. The study of the cellular and molecular contributions of the niche to mammalian HSC production remains restricted to in vivo mouse embryos, which are onerous to manipulate and not amenable to high-throughput screenings. Here, I propose to reconstruct the HSC generating niche in vitro using gastruloids; stem cell aggregates that self-organize into embryo-like structures with spatial and temporal precision. By modifying the original mouse gastruloids protocol, we have been able to recapitulate the emergence of haematopoietic clusters in the wall of vascular structures, with coordinated successive production of haemogenic endothelial and HSC-like cells. By systematically comparing haemogenic gastruloids with embryos I will build on these observations to: 1) obtain a tractable model system that can be used to study the embryonic HSC-forming niche in vitro 2) use this model to study how niche signals regulate HSC formation 3) achieve robust in vitro production of transgene-free, engraftable HSCs. Altogether, I will generate a model that will a) increase our understanding of the HSC niche and b) allow scalable in vitro production of tissue compatible HSCs.
2022
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Long-Term Fellowships - LTF
Defining mechanisms of metabolic-epigenetic crosstalk that drive cancer initiation
XIAO Yi (.)
. - The University of Texas Southwestern Medical Center (UT Southwestern) - Dallas - United States
MCBRAYER Samuel (Host supervisor)
Recent discoveries of recurrent mutations in metabolic genes across human cancers have revealed a central role of altered metabolism in cancer initiation. Pathogenic metabolic gene mutations trigger accumulation of a class of biomolecules called “oncometabolites”, which impair the activities of enzymes that catalyze the demethylation of histones and DNA. Despite these advances, the specific chromosomal regions and genes that represent the functional effectors linking oncometabolites with cancer initiation are poorly understood. This knowledge gap persists in part due to the difficulty of using primary tumor specimens to retrospectively identify mechanisms of malignant transformation. To circumvent this challenge, the host lab has created the first genetically engineered mouse (GEM) model of lower grade glioma driven by the isocitrate dehydrogenase 1 (IDH1) R132H mutant oncoprotein, which produces the oncometabolite R-2-hydroxyglutarate (R-2HG). I propose to use this model together with isogenic, IDH1 wild-type companion GEM models to elucidate the dynamics of changes in chromatin structure, gene expression, and cell populations induced by R-2HG in vivo. I will conduct ATAC-seq, bulk RNA-seq, and single-cell RNA-seq analyses of engineered neural cells isolated throughout the process of metabolism-dependent malignant transformation. My studies will provide a conceptual framework for understanding the deterministic and stochastic functions of oncometabolite signaling to chromatin. My studies will also identify specific oncogenic mechanisms that operate at the interface of metabolome and epigenome to drive malignancy, which could nominate new therapeutic targets in glioma.
2022
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Long-Term Fellowships - LTF
Molecular and material design principles for meiotic microtubule-organizing centers
YAGUCHI Kan (.)
. - The University of Texas Southwestern Medical Center (UT Southwestern) - Dallas - United States
WOODRUFF Jeffrey (Host supervisor)
Formation of viable oocytes requires meiotic microtubule-organizing centers (MMOCs) lacking centrosomes. Multiple MMOCs assemble in oocyte cytoplasm and coalesce at two opposite spindle poles. While much is known about centrosomes, how MMOCs assemble and resist microtubule-mediated stresses is largely unexplored. I hypothesize that MMOC scaffolds begin as liquid droplets formed through demixing of proteins from the cytoplasm (phase separation model). In this case, these scaffold droplets could then fuse with each other and resist forces through regulated material hardening. Alternatively, MMOCs might assemble via diffusion-limited accretion (network percolation model) that require no hardening to resist forces. To test these hypotheses, this proposal aims to quantify the material properties of MMOCs and define the compositions for functional MMOC assembly. First, I will measure the liquidity and strength of MMOCs over time in living C. elegans oocytes. This can be accomplished using an optical technique pioneered in my host lab to induce nano-scale shear force (FLUCS). Second, I will use in vitro reconstitution system combined with FLUCS to determine the minimal protein motifs sufficient for MMOC assembly and material property. The host lab’s unique FlexiBAC expression system allows me to purify truncated candidate proteins known to localize at MMOCs. Finally, I will assess the fidelity of meiotic chromosome segregation when the material properties or components of MMOCs are altered in living oocytes. I expect these results to identify molecular and material designs for MMOC function. They will also represent a key first step toward creating a fully synthetic oocyte.
2022
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Long-Term Fellowships - LTF
Physiological functions and molecular mechanisms of neuronal ER-phagy
YPERMAN Klaas (.)
. - Leibniz-Forschungsinstitut für Molekulare Pharmakologie - Berlin - GERMANY
HAUCKE Volker (Host supervisor)
Neurons are highly polarized cells with a complex architecture that underlies their function in information processing in the brain. The fact that neurons are long-lived post-mitotic cells poses special challenges for the pathways that preserve the integrity of their functional proteome. How neuronal proteostasis is maintained over the lifetime of an organism is a major unanswered question in neuroscience. The proposed project combines and extends my prior expertise in molecular cell biology in plants with recent findings from the host lab to dissect the physiological functions and molecular mechanisms of the turnover of the endoplasmic reticulum (ER), the largest neuronal organelle, via autophagy. Work in the host lab has shown that loss of the essential autophagy protein ATG5 causes the selective accumulation of tubular ER in axons and a concomitant increase in excitatory neurotransmission as a consequence of elevated calcium release from ER stores. Major questions regarding the physiological triggers for neuronal ER-phagy and the machinery involved remain unsolved. In the proposed project, I will use an unbiased proteomic approach utilizing novel proximity labeling strategies to identify the factors that control neuronal ER-phagy in the central nervous system. Moreover, I will develop live correlative light and electron microscopy approaches in genome-engineered mouse hippocampal and stem cell-derived human neurons to unravel the physiological stimuli that trigger axonal ER-phagy. The results obtained will provide fundamental new insights into the role of ER-phagy in maintaining brain function and aid the development of therapies to combat neurodegeneration.
2022
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Long-Term Fellowships - LTF
Development of neural circuits for cooperative behavior in schooling fish
ZADA David (.)
. - The Regents of the University of California, San Diego - La Jolla - United States
LOVETT-BARRON Matthew (Host supervisor)
Throughout the natural world, many species behave in cooperation with their social groups. For example, individuals in a school of fish sense the actions of their neighbors to coordinate their actions. These complex sensory-motor behaviors emerge at the transition to adulthood, but it is unknown how the maturation of an individual’s neural circuits produces the capacity for social coordination. Here we propose a novel approach to study the functional development of neural circuits underlying social attention in schooling fish, using large-scale cellular-level calcium imaging and immersive virtual reality. We will apply these technologies to the micro Danionella translucida; glassfish remain small and transparent throughout their lifespan, allowing for whole-brain neural activity imaging in socially-mature animals. We will engage Danionella in a head-tethered virtual reality environment, where we can image neurons across the brain as fish move their tail to navigate a panoramic visual environment with an interactive group of computer-simulated schooling fish. We will record cellular-level calcium activity from across the visual-motor circuits of transgenic Danionella expressing a genetically-encoded calcium indicator in all neurons, and identify cells that encode the actions of others in the social group. By imaging from early development to mature adult, we will identify the developmental onset of socially-encoding neural circuits and schooling behavior. Overall, this new research direction will provide foundational insights into the function and evolution of the social brain, and identify how these abilities emerge from neural circuit development and maturation.