We propose to unravel a long-standing mystery in neuroscience: the origin and functionality of endogenous extracellular electric field in the brain. While neuroscientists have heavily relied on extracellular recordings to study mechanisms of brain processing very few have addressed their identity. We focus on the local field potential (LFP), the slow portion of the recorded extracellular voltage (Ve), thought to reflect neural circuit computations. We seek to quantitatively understand the origin of the LFP in neocortical and hippocampal structures and to manipulate such fields to characterize the extent to which these can directly affect the state and function of neurons and neural populations through field (ephaptic) effects. We do so in a highly interdisciplinary manner allowing us to study these effects in multiple scales. We will use novel multi-patch setups, silicon probe recordings, optical stimulation protocols to obtain intra- and extracellular recordings at multiple locations in- and outside neurons both in the hippocampus and the neocortex to understand the origin of extracellular fields induced by different neural types and the contribution of compartments such as the soma or dendrites. Concurrently, optical stimulation, transcranial electric stimulation and massively parallel recordings will be conducted to study Ve and the endogenous field in anesthetized and behaving rodents. In addition to the experiments, we plan to carry out biophysical simulations of individual neurons as well as neocortical and hippocampal circuits to understand the origin of Ve (and the LFP in particular) by examining various Ve-contributors such as postsynaptic currents from pyramidal neurons and other neural types. Finally, we seek to provide a theoretical framework to address the extent to which endogenous electric fields can alter or entrain the activity of a neural circuit via ephaptic coupling both in terms of subthreshold and spiking activity.

The kidneys are essential organs required for excretion of waste products and the regulation of fluid balance, blood pressure, blood volume, ion balance and bone density. The functional units of the kidney are the epithelial nephrons which can filter the entire blood volume every minute, creating 200 litres of filtrate each day and then recapturing 95% of this volume. All of the nephrons form during fetal development from two key stem/progenitor populations that interact with each other to form the intricately branched plumbing of the kidney as well as the filtering tubules. In humans, the number of nephrons per kidney varies 9 fold between individuals and there is an inverse correlation between nephron number and the likelihood of hypertension and kidney disease later in life. While much of kidney development has been described anatomically, due to a lack of quantitative and spatial modeling of this complex process across the fetal development, there is little understanding of how such variation in kidney size and nephron number can come about. The purpose of this application is to bring together mathematical modeling, advanced imaging and developmental genetics in order to develop a comprehensive model of the process of kidney development. Having created a framework that predicts the interactions between different cell types, we will test and refine this model by genetically altering the size of different cell populations to see how this affects development and whether the model holds. This will ultimately allow us to predict the outcome of perturbations in different cell compartments over space and time and potentially guide us with respect to understanding why nephron formation ends and what parameters might need to be altered to prolong the process.

The three-dimensional organization of the genome plays important and yet poorly understood roles in its regulation including control of gene expression and genome segregation. Control of gene expression by distantly located regulatory elements involves formation of chromatin loops driven by physical promoter-element interactions. Moreover, active and inactive segments of the genome appear spatially separated, which may contribute to their coordinated expression or silencing. Finally, formation of complex higher-order chromosome structures plays critical roles in chromosome condensation and segregation during mitosis. Thus, chromosomes assume multiple distinct conformations in relation to the expression status of resident genes, and undergo dramatic alterations in higher-order structure throughput the cell cycle. Detailed insights into chromosome conformation will greatly contribute to a more complete characterization of genome regulation.

Our aim is to combine light microscopy, cell and molecular biology with physics and statistics to determine a probabilistic map of the organization of chromatin domains in intact cells during cell cycle and in relation to gene expression. This project breaks important new ground by deriving high-resolution three-dimensional structures of higher-order chromatin organization and by discovering how these structures change dynamically during the cell cycle. This work will allow the characterization of the dynamics of higher-order chromatin folding and the identification of specific roles of genomic elements in these processes.

Lesions of the spinal cord or pathologies involving spinal motoneurons (such as amyotrophic lateral sclerosis, ALS) lead to partial or complete impairment of motor function in humans. Electrical stimulation of the spinal cord has been used both for diagnostic and rehabilitative purposes when spinal cord function has been compromised. It has also been an important basic research tool for exploring spinal cord function [1,2]. Nevertheless, electrical stimulation suffers from the disadvantage that current spreads in a highly non-specific manner, activating all nearby fibers of passage and making it difficult to isolate the effects of stimulation [3]. Optical stimulation of the spinal cord has the potential to overcome this drawback, as specific classes of spinal neurons can be focally targeted for excitation or inhibition. Given the considerable complexity of spinal circuits, the ability to focally activate specific sub-population of neurons is crucial to understanding overall spinal circuit function. Specifically, I begin with the hypothesis that the spinal cord is organized at the level of modules that control muscle activations in terms of functional groupings or “synergies” [4]. Where and how are these synergies constructed? Are they invariant or can they be modulated in a context-dependent fashion? I propose to investigate the hypothesis that synergies arise solely from the dynamics of inter-neuronal circuitry. This hypothesis can be rigorously tested by optogenetic manipulations of selectively targeted classes of neurons within the spinal cord.

The success of humans greatly relies on our ability to understand and manipulate our environment. The use of other life forms is no exception, though for ages this process resulted mostly from unconscious domestication. Spectacular advances in molecular biology now makes it theoretically possible to genetically modify existing organism, and particularly microbes, to endow them with new functionalities.
However impressive, our technical abilities to physically manipulate DNA largely exceed our understanding of the underlying genetic systems. The emerging field of synthetic biology aims at providing scientific tools to bridge this gap and make biology easier to engineer – be it for academic or technological applications.
A major roadblock is that the basic components specifying the expression of genetic informations are not described in a manner that support their rational use. Indeed, studies generally provide exquisitely refined descriptions of paradigmatic examples, analyzed in a single genetic context. As a result, most attempts to construct a particular genetic system with a defined output require a wasteful cycles of trial and errors.
The aim of this project is to analyze the activity of a large number of natural and engineered genetic components involved in gene expression, and to describe their interactions when composed with each others. The experimental data will be used to build predictive models linking sequences and activities. Beyond deepening our fundamental understanding of the central dogma, these results will be used to devise strategies to minimize interactions between components, thereby enabling their rational combination toward a predicted output.

The goal of this project is to understand how the HIV-1 virus that causes AIDS escapes from infected cells. Formation of retroviruses such as HIV-1 is an interplay between the multidomain viral protein Gag, plasma membrane lipids, and cellular proteins of the ESCRT machinery. Gag assembles into an ordered lattice on the inner face of the plasma membrane and recruits other components of the virus. Release of the nascent virus particle is not mediated by the viral proteins themselves, but by the cellular ESCRT complexes which are recruited by Gag to the budding site. In order to understand in detail how this happens, HIV-1 assembly and release will be reconstituted from the individual viral and cellular proteins and model membranes that mimic the plasma membrane. The Gag polyprotein and the individual human ESCRT complexes will be purified and fluorescently labeled. The proteins will be assembled in a sequential fashion on giant unilamellar vesicles (GUVs) and the ensuing formation of viral particles will be analyzed in real time by fluorescence microscopy. This will allow definition of the minimal protein machinery necessary for HIV formation, clarify what role specific lipids play in the membrane bending and scission, and possibly generate new strategies to inhibiting HIV release. The proposed reconstitution of HIV formation is a novel approach to study this process, and will provide a higher level of detail about the mechanism of enveloped virus assembly and release than has ever before been possible.

Our history is imprinted in our genes: population structure and ancient migrations were found to be encoded in human genetic variation. With the revolution of high-throughput DNA genotyping and sequencing, history can now be uncovered in unprecedented detail.

I propose to develop new tools for geography-based historical reconstruction. Contrast to previous approaches, I will use sharing analysis- the study of the lengths of genomic segments shared between individuals. Recent algorithmic breakthrough of the host lab, combined with data from new sequencing technologies, enable now the use of this method, which is expected to be more informative compared to other approaches.

My first goal will be the application of sharing analysis to globally distributed populations. I will then attempt to explain the observed sharing statistics by constructing a geographical model that involves a series of colonization events. I will determine parameters such as migration and admixture rates and bottleneck sizes as those that best fit the data. I will also use our model to resolve long-standing debates over the nature of the distribution of migration rates.

I will also investigate Jewish genetics, for which the host lab has exclusive access to the largest existing collection of genetic variation data. I will study for the first time the relation between Jewish genetics and geography and create geographical models accordingly. Particular properties of Jewish history make its modeling in some cases relatively easy (e.g., one dimensional), and thus, models will be made highly detailed.

In the mammalian olfactory system, odor information is transmitted to the main olfactory bulb (MOB) by the axons of olfactory sensory neurons (OSNs). OSN axons expressing a particular olfactory receptor project to just one or two glomeruli in each hemisphere of the MOB. The glomerular input layer of the MOB is therefore the initial site for processing of odor information. Individual glomeruli are interconnected by the axons of a recently characterised class of dopaminergic (DAergic) periglomerular/short-axon cells. It is clear that the function of DAergic neurons is strongly activity-dependent, as blocking olfactory sensory input results in a dramatic reduction in both tyrosine hydroxylase expression and dopamine production. However, the role of DAergic neuron-mediated interglomerular connections in olfactory processing in the MOB remains poorly understood. This project will utilise recently developed genetic tools that enable specific labelling and activation of DAergic neurons. A combination of electrophysiological and state-of-the-art optogenetic techniques will be employed both in brain slices and in vivo, to investigate the role of DAergic neurons in sensory integration in the MOB, and the activity-dependence of the interglomerular projections that they form. It is envisaged that the results obtained will provide important insights into the mechanisms and activity-dependence of sensory integration in the MOB. Moreover, this study may also provide new diagnostic and therapeutic strategies for a range of neurological and psychiatric conditions in which both olfactory dysfunction and dysregulation of DAergic transmission are features.

Epithelia are fundamental elements of many tissues and organs. During embryo development they undergo a complex pattern of shape changes and display a remarkable dual feature of robustness and plasticity. How epithelia maintain an accurate equilibrium between these two apparently contradictory properties during morphogenesis is unclear. I will address this question using germ band extension (GBE) in the Drosophila embryo as a model system. Here cells intercalate by exchange of their neighbours without losing cohesion. This is achieved by a planar polarized pattern of cell junctions remodelling driven by anisotropic actomyosin mediated contractility. The aim of this proposal is to understand the molecular and cellular basis of junction remodelling with an emphasis on how adhesion and contractility are co-ordinated. To this end I will first characterize fluxes of E-cadherin during junction remodelling in intercalating cells, then I will systematically analyze their interplay with the actomyosin system and finally I will undertake an unbiased approach to identify genes responsible of the specific E-cadherin and actomyosin patterns in intercalating cells. This project is expected to shed more light on how adhesion and contractility are integrated and on the mechanisms of new junction formation. This fellowship will expand my expertise in membrane trafficking in mammalian cells with genetics, cell mechanics and Drosophila as a new model system. In this way I will be able to combine my knowledge of the organization of intracellular systems in cells to the problem of the organization of cells into tissues, the topic I wish to pursue in my future career.

Birds are among the most colorful of vertebrate species, and most birds live in visually rich habitats. Not surprisingly, the avian retina is endowed with one of the most sophisticated cone photoreceptor systems of any vertebrate. Yet, despite this richness, the various optical adaptations of avian cones remain poorly understood. Our lack of knowledge stems, in part, from the fact that most studies of the visual system have focused on mammalian retina. In addition, studies of avian cone function have been hampered by the lack of model systems amenable to molecular/genetic manipulation. For this reason, almost all studies of bird vision have been restricted to wild-type animals. The overarching goal of this proposal is to deconstruct the optical adaptations of avian cone photoreceptors via an interdisciplinary combination of molecular genetics, optical physics, computer modeling and vision-guided behavioral assays in chickens. We plan to co-opt molecular/genetic techniques originally developed in the chicken to study embryogenesis, and use them to engineer post-hatch birds with modified cone photoreceptors. We will then apply cutting-edge optical analysis and modeling to both wild-type and genetically modified photoreceptors to elucidate their adaptations for light handling. Lastly, we will implement innovative vision-guided behavioral assays in newly hatched birds to link the genetic modifications and their optical effects to the resultant functional changes in vision. These studies will shed light on a range of amazing optical adaptations found in avian cones which are either absent or poorly developed in mammals and will thus reveal new insights into the visual world of birds.

The compaction of chromatin governs DNA accessibility and therefore has a crucial function in establishing, maintaining and propagating distinct patterns of gene expression. The opposing activities of Polycomb group (PcG) and trithorax group (trxG) proteins are part of a chromatin regulation system, ensuring the correct expression of specific transcriptional programs at defined developmental stages.

PcG-proteins form chromatin-modifying complexes that implement transcriptional silencing in higher eukaryotes. Three different PcG-protein complexes have been isolated from Drosophila: the Polycomb Repressive Complex 1 (PRC1), PRC2, and the PcG Protein Polycomplike (Pcl-PRC2). The characterization of several PRC2 components in Arabidopsis constituted a first breakthrough, revealing key roles of PcG-proteins in the control of crucial plant developmental processes.

Transcriptional networks play a primary role in regulating development in both plants and animals. The Arabidopsis root is ideally suited to study the effect of PcG-proteins on the transcriptional networks. Using a combination of systems biology, genomics and genetic approaches, we aim at determining the upstream and downstream components of the PRC2 regulatory network in acquisition of root cell type-identity in Arabidopsis.

Asymmetric cell division (ACD) gives rise to two daughter cells, which inherit different determinants, thereby acquiring different fates. Reports in Drosophila showed that during ACD, Notch and its receptor Delta traffic through specific compartments, the Sara endososomes, which are targeted towards only one of the daughter cells, thus contributing to define the Notch signalling-receiving cell. Unpublished observations suggest that Sara endosomes are able to ‘read’ a polarity signal 'written' on the spindle by means of a gradient of tubulin acetylation. This project addresses three key questions: i) what is the full machinery controlling the directional motility of Sara endosomes during ACD? ii) how do motors present at the surface of Sara endosomes ‘read’ the gradient of acetylation? iii) how does interfering with tubulin acetylation in space and time affect the motility of Sara endosomes during ACD? To achieve my goals, I will use an interdisciplinary approach integrating biochemical reconstitutions with experiments in cultured cells and in the whole organism. In particular, I will use microfluidics to engineer microtubules presenting a controlled pattern of acetylation, which will allow me to directly address how tubulin acetylation affects the motility of isolated endosomes and the behavior of motors at the single molecule level. In addition, I will develop a tubulin acetylation biosensor and photoactivable enzymes to monitor and interfere with microtubule acetylation in vivo. This innovative project is poised to shed new light on directional signaling during asymmetric cell division, as well as on the role of tubulin post-translational modifications.

Cyclic expression of genes (i.e. oscillation) is involved in basic processes such as cell-cycle and circadian clock. The molecular mechanisms behind the generation of these oscillations are being elucidated and have led to the identification of “biological clocks” in different biological processes. Ultradian oscillations, i.e. with periods much less than 24 hours, at the molecular level have been observed also in the major signaling pathways, but their relevance is still unclear. We hypothesise that one of the roles of cell signaling is to allow "mutual synchronisation" and "entrainment" of these oscillations across a tissue for robust coordination of biological processes at the tissue-level. Mutual synchronisation of oscillations happens when different “biological clocks” start “beating in time” by spontaneously synchronizing their oscillations via some form of cell-cell coupling, which we hypothesise may be mediated by cell-cell signaling. Entrainment refers to the existence of an external “pace-maker” signal that drives the individual clocks and forces them to beat in time. In this project we will investigate, via an integrated mathematical and experimental approach, the biological mechanisms of entrainment and mutual synchronization of cell-autonomous oscillators involved in signaling. Our objectives are: (1) to characterise, via mathematical modeling, entrainment and mutual synchronization of a population of cell-autonomous oscillators, using recent results from dynamical systems theory and numerical simulations; (2) to use synthetic biology to implement a synthetic cell-autonomous oscillator in mammalian cells to experimentally test entrainment and mutual synchronization, in the context of a well characterized oscillator mechanism; (3) to test the physiological relevance of entrainment and mutual synchronisaton of cyclic gene expression/protein localisation in mammalian cells. We will consider four examples: (i) the hes1-oscillator. We will investigate the 2-hour periodic expression of Notch signaling molecules in different cellular models, where these oscillations are known to occur. (ii) The p53-oscillator. We will focus on the tumor suppressor gene p53, which exhibits oscillations in its expression in individual cells. (iii) The Smad-oscillator. This refers to the cyclic nuclear shuttling of Smad proteins following stimulation by TGFb and serum. (iv) The Stat-oscillator. This is another example of cyclic nuclear shuttling following cytokine stimulation. The experimental protocol will require the determination of the fluorescence intensity in live cells as a function of time, at single cell resolution, and the ability to deliver periodic perturbations to the cells in the form of precisely controlled time-varying concentration of inducer molecules. To this end, we will develop innovative microfluidic ‘lab-on-a- chip’ devices in conjunction with time-lapse microscopy. These devices are able to trap single cells, or small populations of cells, for long-term data acquisition and to precisely control the extracellular environment. The output of this project will be to characterise oscillatory behaviour of genes involved in signaling in a cell population. By investigating different signaling pathways, where oscillations in expression or localization of proteins are known to occur, we will be able to understand whether different kinds of cell-autonomous oscillators make use of similar principle for their entrainment and synchronization, or on the contrary, they exhibit very different properties and rely on different mechanisms.

Melanoma is a particularly invasive and aggressive cancer that exhibits high degree of plasticity and resistance to chemotherapeutic drugs. Melanoma cells possess many features of stem cells including self-renewal capacity, high tumorigenicity and differentiation potential into various lineages. Subpopulations of cells with stem cell properties have been isolated from human melanomas, although at variable frequency depending on the criteria used. Thus, alterations in key regulators of normal melanocytic differentiation may contribute to melanoma initiation/progression. MicroRNAs (miRNAs) are endogenous non-coding small RNAs that play important regulatory roles in different biological processes such as normal cellular development and tissue homeostasis. MiRNAs are altered during melanoma pathogenesis and this alteration correlates with increased proliferation, increased survival, loss-of-differentiation and enhanced migratory capacity. Here, I propose to perform a high-throughput expression screening to identify miRNAs that may affect in vitro differentiation of human embryonic stem cells towards melanocytes. Positive hits (miRNAs that block melanoblast differentiation) will be tested in vivo in an established mouse model of skin re-pigmentation. Furthermore, I will manipulate the expression of the identified miRNAs to test whether imposing an undifferentiated status on melanocytes enhances melanoma-susceptibility and/ or progression. My findings will unravel molecular mechanisms of stem cell and melanocytes biology and provide novel insights on the role of miRNAs in differentiation and cancer.

The research interest in bioluminescence – light emission from chemically produced excited states observed with bacteria, fungi and invertebrates, has been revived recently due to its immense potentials for application to novel ultrasensitive bioanalytical techniques, which include in vivo bioluminescence imaging, gene expression and trace ATP analysis. The firm prospects for further growth of this frontier research field are founded on the requirement for energy-rich factors (ATP) and the highest fluorescence yields observed with the firefly luciferases among all known natural and artificial luminescent reactions based on matrix-unbound emitters. Most of the natural members in the large family of beetle (including the firefly) activated luciferin/luciferase complexes emit yellow-green light, although orange- or red-emitting wild-type and mutant cases have also been isolated and cloned. Yet, the complex chemical equilibrium (six chemical forms) and the pronounced in vitro instability of the emitter, oxyluciferin, have imposed great impediments to the efforts at attaining fundamental understanding of the nature of its excited-state structure and photochemistry. Albeit no less than six mechanisms of color tuning have been proposed, the long-standing conundrum about the molecular-level origin of different color emissions has yet to be resolved.

This project focuses on the excited-state structure and photochemistry of oxyluciferin. We aim at unraveling the exact structural factors that affect the emitted light, and we intend to apply the inferences to assess the performance of purposefully modified emitters for novel biochemical applications. Fundamentally new synthetic strategies will be developed to access a large variety of non-natural oxyluciferins, their precursors and isotopically labeled variants. The oxyluciferin photochemistry will be studied in/ex situ at single-molecule/ensemble/crystal level in solution and under a microscope with a set of unconventional spectroscopic and X-ray photodiffraction techniques.

Although its biological functions remain unknown, sleep is important for memory formation in a variety of animal species including humans, mice, and fruit flies. While sleep influences both the acquisition of new memories and the consolidation of recently formed associations in the fruit fly Drosophila melanogaster, the functional role of sleep in these processes is not understood. To compare the effects of sleep deprivation on memory acquisition and consolidation in the fly more directly, I will test the consequences of sleep loss on memory in an olfactory conditioning assay in which flies are trained and tested individually. Dopamine signaling is necessary for the formation of aversive associations during olfactory conditioning, and is dysregulated following sleep deprivation. Recent studies have identified a single cluster of dopaminergic neurons, the PPL1 cells, which signal unexpected punishment to the MBs and thereby drive associative olfactory conditioning. The PPL1 neuron–MB circuit is thus a likely site of functional impairment following sleep loss. To characterize the effects of sleep deprivation on the functioning of this circuit, I will use 2-photon microscopy and electrophysiology to observe PPL1 activity in sleep deprived flies and rested controls. During the memory consolidation phase, I will also observe the activity of the dorsal paired medial neurons, whose action is required for the formation of long term memory. This proposal will provide an opportunity to further my training in both sleep and memory research and apply recently developed imaging techniques to examine the neurophysiological consequences of sleep loss on memory-related circuitry.

Bacteria can survive on their own, yet in natural environments they are rarely alone. Indeed certain types of bacterial behavior, such as biofilm formation and bioluminescence, require a high concentration of bacteria as well as some form of coordination among the participants. Vibrio species can achieve this coordination by sensing the communication molecules released by organisms of the same species, other Vibrio species, and bacteria of different genera. These sensing capabilities hint at a rich variety of cell-cell interactions, the full implications of which have yet to be determined. We will investigate spatial and temporal aspects of such interactions in Vibrio species, by studying the population spatial structure of Vibrio harveyi, Vibrio cholerae, and mixed suspensions, while the population transitions to social behavior in highly controlled microscopic environments. Tracking single cells in populations, and simultaneously measuring the expression level of genes responsible for social behavior in each cell, will allow us to answer the following questions: Do all cells participate in social behavior? Is the transition to social behavior synchronous? Do chemotaxis and the dynamics of active suspensions lead to clusters or other spatial structures that locally initiate social behaviors? How do suspensions of mixed species organize spatially during social behaviors? We will also develop mathematical models to understand the population-level behavior. The inputs for these models will be measured in another line of experiments, which will include a quantitative characterization of the temporal aspects of the communication signal transduction pathways.

Secreted TGF-b family proteins play key roles in cell differentiation in metazoan organisms. Of great interest, TGF-b proteins drive epithelial-mesenchymal transition (EMT), which plays a key role throughout development and in cancer progression. TGF-b proteins induce changes in gene expression through Smads, which act as transcription regulators. Smads are phosphorylated by TGF-b receptors, and their activities are further regulated through phosphorylation by other kinases. Since protein methylation has been emerging as a post-translational modification that defines protein function, and epigenetic regulation of histone methylation provides a platform for interactions of transcription factors with methylated histones or associated proteins, we hypothesize that interactions of methyltransferases with Smads may play key roles in the TGF-b signaling response. However, up to now, there is no knowledge on the role of methyltransferases in TGF-b family signaling or on functional interactions of Smads with methyltransferases. Through my recent research, I found that Smad3, the major effector Smad for TGF-b signaling, can be methylated and that the methyltransferase ESET interacts specifically with Smad3. I now propose to biochemically and functionally define the interaction of ESET with Smad3 in TGF-b signaling, using the SnoN gene as model target for Smad3-ESET. I hypothesize that functional interactions of Smad3 with ESET define TGF-b signaling and TGF-b-induced transcription regulation through methylation of Smad3, and/or ESET-mediated changes in histone methylation. I will then examine the role of the functional interaction of ESET with Smad3 in TGF-b-induced EMT.

Biofilms form when bacteria attach to a surface and secrete sticky polymeric substances and are of enormous importance in nature, industry and medicine. While nearly all of our knowledge about these communities has been gleaned from biofilms growing on planar surfaces (i.e. agar plates and within flow cells), in many natural systems cells grow in topologically complex environments where there is the potential for strong interactions between fluid motion and growth. These interactions can result in preferential flow channels and large unirrigated regions, the physical and evolutionary implications of which are largely unknown. I propose a combined experimental and theoretical investigation of biofilm development and evolution in heterogeneous environments. Using custom microfluidic channels that simulate a porous media environment, I will characterize how key factors including fluid flow, nutrient loading and bacterial genotype shape patterns of biofilm development. The dominant physical processes will be rationalized using a nondimensional network model. The system will then be used to elucidate interactions between fluid dynamics and evolutionary dynamics and, in particular, social evolution. Efficient biofilm growth requires cell cooperativity. I will study how preferential fluid channel formation affects cooperation, and vice versa, by competing bacterial strains that differ in their level of cooperativity. As a fluid dynamicist who has worked primarily on the motility of marine phytoplankton, this project will represent a significant change in research direction and offer me extensive exposure to evolutionary theory, microbiology and molecular genetics.

Glycogen, the glucose storage molecule, is considered an invaluable asset for cells. Glycogen Storage Diseases (GSDs) are pathologies linked to mutations of the genes in the glycogen metabolism pathway. Symptoms vary from mild metabolic defects to severe degenerative processes. The glycogen found in these disorders is abnormal in quantity, quality, or both. Our hypothesis is that these glycogen molecules harm the cell.

Wild-type glycogen branching enzyme (GBE1) deficiency (Andersen Disease, Adult Polyglucosan Body Disease (APBD)) results in the accumulation of aggregates of linear glycogen. We aim to identify the mechanisms by which such aggregates trigger cell dysfunction and death. To this end, we will model the impact of mutations found in patients on GBE1 structure and function. Using animal and in silico models, we will study the effects of abnormal glycogen accumulation on energy metabolism, mitochondrial function and cell viability. Involving techniques from biology, biophysics and chemistry, this project will reveal the deleterious effects of a molecule, glycogen, generally considered advantageous, and may offer new clues for the treatment of APBD and other GSDs.