- Total grants
- Total funders
- Total recipients
- Earliest award date
- 11 Jan 2016
- Latest award date
- 06 Dec 2016
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
A Symposium on Enhancing Engagement, Co-production, and Collaborative Meaning-Making in Qualitative Health Research 30 Jun 2016
Traditional "lone researcher" models of qualitative research have shifted to include more collaborative ways of researching, with research participants and other stakeholders viewed as partners in the co-production of knowledge. As well as working alongside "lay researchers", qualitative researchers increasingly work in teams with colleagues unfamiliar with qualitative methods. This is largely driven by calls to engage the public in the production of knowledge and penetrate borders between disciplines. As a result, research is assumed to become more relevant to users’ needs, ethical, and broadly applicable, and is key to requirements of funding bodies and the Research Excellence Framework. However, such collaboration is complex and creates challenges for qualitative researchers. We will explore these issues in a one-day symposium hosted by University College London (UCL), and attended by 150 UK and international delegates. The symposium will provide a platform to develop critical perspectives on: How collaborative relationships are established and embedded, and particularly how qualitative researchers are positioned in multidisciplinary teams; How research designs, data interpretation and reporting are negotiated and enacted; The extent to which "lay researchers" offer the views and experiences of groups they represent and how marginalised groups are accommodated. Keywords: qualitative research, health, collaboration, engagement, symposium
Embryonic stem cells are pluripotent cells that can give rise to the three germ layers. Evidence indicates they can maintain pluripotency whilst giving rise to progenitor cells for all the embryo cells, suggesting that they are capable of asymmetric division. However, the cell biology of embryonic stem cell division is poorly understood. Interestingly, embryonic stem cells have mechanical properties very different from their differentiated counterparts, and their fate is strongly influenced by the mechanical properties of the substrate, suggesting that stem cell division might be asymmetric with respect to daughter cell mechanics. We propose to explore the geometry, mechanics and physical control by the environment of stem cell division using mouse embryonic stem cells as a model. We will follow cell division and the fate of the daughter cells at the single cell level and in colonies. Altogether, this project will broaden our understanding of the molecular and biophysical control of embryonic stem cell division, a process key to stem cell homeostasis and embryonic development, and will clarify how cell shape and mechanics influence embryonic stem cell fate.
Genome-wide association studies (GWAS) have greatly improved our understanding of human disease genetics, and are beginning to be applied to pathogens. Current pathogen GWAS have largely focused on the identification of variants behind bacteria and parasite drug resistance. A neglected application is identifying variants determining infectiousness for viruses such as HIV-1. HIV transmission is influenced in large part by an individual’s set point viral load (spVL), which itself is determined by variation in the viral genome. Given HIV’s short genome and large amount of common genetic diversity, spVL provides a tractable target in terms of potential pathogen GWAS with large global health implications. During this fellowship I will first adapt GWAS to HIV whole genome sequences by focusing on drug resistance, a phenotype where many variants are already well understood. Once the methods are perfected, I will analyse spVL in the PANGEA_HIV sample of 20,000 whole genome sequences. Identified variants will be combined with demographic data to understand how they influence transmission on a population level. They will also be tested for interactions with host genetic variants, to understand the biology of immune escape. This will allow for a better understanding of transmission risk.
Signalling pathways orchestrate almost all aspects of development. The Schier lab has recently used ribosome profiling to identify numerous previously uncharacterised proteins that are expressed during early embryogenesis in zebrafish and might function as signalling molecules. One of the novel signalling proteins, previously annotated as a non-coding RNA, is Toddler (also called Apela or Elabela). Toddler signals via the APJ/Apelin receptor and promotes cell movement during gastrulation. The cellular and molecular roles of Toddler signalling are not known. My first aim as a Sir Henry Wellcome postdoctoral fellow will be to identify proteins that are regulated by Toddler signalling and reveal the cellular mechanisms that mediate the motogenic function of Toddler. My second aim is to employ a similar ribosome profiling approach to discover uncharacterised signalling molecules involved in the development of the nervous system. I will use genome engineering and take advantage of the complementary experience and expertise of the Schier and Wilson labs in behavioural and neuroanatomical studies to identify and analyse these signals. Their cellular and molecular functions will then be investigated. This project has the potential to discover signals with essential roles in neuronal migration, specification of neuronal identity and diversity, circuit formation and function.
Transforming visual images to cognitive maps 24 Feb 2016
The visual system and hippocampal formation are two of the most studied areas of the brain. However, we do not understand how these areas work together. My goal is to understand the neural circuits and computations through which signals from sensory visual images are progressively transformed to create a cognitive map. Specifically, I will test the hypothesis that visual signals are processed along two parallel streams for navigation: one which processes landmark related signals, and a second stream that processes signals related to self-movement. I will then test two specific hypotheses regarding how the hippocampus integrates signals from multiple sources. Finally, I will test the causal influence of specific pathways on the hippocampal representation of space and animals’ spatial decisions, by inactivations using opto-genetics. I will address these questions in mice, using techniques such as rodent virtual reality, large-scale electrophysiology recording, computational modeling, and optogenetic interventions. My key goals are: 1) Identify the circuits involved in creating a cognitive representation from visual images. 2) Determine the computations by which visual signals are transformed into cognitive signals. 3) Understand how the hippocampus combines signals from multiple streams, and is affected by manipulations to pathways of the vision-to-navigation circuit.
Fatigue in neurological conditions, unlike exercise induced fatigue, is chronic, irreversible and does not arise from altered sensory afferent input from peripheral musculature. A distinctive feature of such fatigue is requirement of high effort for everyday activity. Normally, everyday activity feels relatively effortless. This is due to re-afferent sensory feedback from voluntary movement being attenuated under normal circumstances (sensory attenuation). I propose that neurological perceptual fatigue is a result of poor attenuation of re-afferent sensory feedback making even the simplest of movements feel effortful. Using a combination of behavioural and electroencephalography techniques, in a series of systematic experiments, I will study the interaction between self-reported fatigue, effort, behavioural and neural correlates of sensory attenuation. Furthermore, using brain stimulation techniques I will modulate sensory attenuation to determine the direction of causality between fatigue and neural processing. I will study chronic stroke survivors where post-stroke fatigue is a major problem. Fatigue is commonly seen as a neuropsychiatric symptom in neurological conditions and what I propose is a significant shift away from fatigue as a psychiatric problem and towards neurological fatigue being a sensorimotor disorder. The proposed project is also likely to identify a potential therapeutic target to develop interventions for neurological fatigue.
The neural circuits of social preference 01 Jun 2016
Social preference requires the ability to recognize and approach individuals of the same species (conspecifics). In humans, these behaviours are present from birth and are thought to be impaired in developmental disorders, such as autism, that are characterized by aberrant sociality. The innate brain circuitry that underlies human social preference is conserved in other social vertebrates, including the genetically accessible zebrafish. I have recently shown that larval zebrafish exhibit social preference from just two weeks post fertilization. At this developmental stage, larvae are transparent and thus amenable to the full range of modern optical techniques for single cell resolution circuit analysis. I will first use reporters that integrate neural activity to highlight the anatomical correlates of the social preference circuit. Two-photon calcium imaging during the presentation of virtual social stimuli will then be used to characterize the functional properties of the identified circuit elements. Finally, given that fish development occurs ex utero, I will monitor the development of this essential circuit and precisely document the impact of environmental and genetic manipulations that have been implicated in models of human disease.
HIV pathology precipitates irreversible loss of mucosal barrier integrity. Innate Lymphoid Cells (ILCs) are crucial for rapid tissue repair and homeostasis and stimulate epithelial cell proliferation at gut mucosal barrier sites. I have shown that HIV-1 infection depletes ILCs in the circulation, and that this depletion correlates with disease stage and is not restored by antiretroviral treatment (ART) in chronic infection. Critically, ART initiated during early acute infection prior to peak viremia preserved ILC depletion1. This is a strong rationale for a role of ILCs in HIV pathology that involves gut barrier breakdown. However, the impact on ILC function at mucosal gut barrier sites remains unclear and is the specific focus of this proposal through studies of unique gut samples not available in Europe and US. Goals: 1: To define the role of ILCs in gut barrier integrity during different stages of HIV infection and study the impact of ART treatment. 2: To study the impact on gut epithelial cells after HIV infection and investigate those mechanisms using the "mini-gut model". 3: To use ILC and epithelial cell interaction as a first step to develop a novel treatment strategy focused on restoring gut dysbiosis to prevent immune activation and AIDS.
This research programme is designed to explore cellular and molecular mechanisms underlying homeostatic metabolic control of regional brain blood flow by addressing the following fundamental questions: (Q1) How are the changes in brain parenchymal PCO2/[H+] detected and what are the mechanisms underlying the effect of CO2/H+ on cerebral vasculature? (Q2) What are the mechanisms responsible for hypoxia-induced dilation of cerebral vasculature and what is their role in the redistribution of regional brain blood flow in accord with parenchymal O2 content? (Q3) What is the role of CO2/H+-sensitive mechanisms of astroglial/vascular interface in neuronal activity-dependent control of cerebral vasculature and in generation of the blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) signals? (Q4) What are the cellular identity, sensory transduction mechanism and physiological role of an intracranial baroreceptor capable of sensing decreases in brain perfusion pressure? These questions are addressed by genetic targeting and blockade of hypothesized signalling pathways, in vivo two-photon excitation imaging of neurovascular interface ([Ca2+]i in astrocytes/neurones and parenchymal vasculature) and assessment of regional cerebral blood flow and cerebrovascular reactivity using BOLD and arterial spin labelling fMRI in experimental animals (rats and mice).
Our goal is to understand how cells make stochastic cell fate decisions in development and dedifferentiation. Understanding how individual cells make decisions has until recently been intractable, because gene expression has been measured from population averages. These averages mask the dynamics and differences between cells that define development or dedifferentiation in complex cell populations. Recently, we have pioneered approaches to visualize the transcription of individual genes in single, living cells. This means we can continually monitor the expression of cell fate regulators in single cells as they commit to fate decisions. We will now combine our imaging methods with molecular genetics, to test the hypothesis that stochastic cell fate choices in development are derived from heterogeneity in the expression of cell fate regulators. To determine how cells overcome the rate-limiting steps in dedifferentiation, we will use our technologies to dissect the gene expression dynamics required for successful reversal of the differentiated state. Overall our work will define the fundamental characteristics of the gene expression underlying stochastic fate choices in development, and provide new directions for developing safe, effective regenerative medicine.
Neural Circuits for Selective Auditory Filtering 05 Apr 2016
To facilitate sensory processing in complex environments, the brain can selectively filter auditory input to enhance neural responses to relevant sounds and suppress responses to background distractors. Neural correlates of selective filtering have been observed in auditory cortex (AC), but the underlying neural circuitry has not yet been identified. A synthesis of existing results and our preliminary data suggests that selective auditory filtering arises through interactions between AC and two thalamic structures: the medial geniculate body (MGB), which sends direct excitatory input to AC and receives direct excitatory feedback from AC, and the thalamic reticular nucleus (TRN), which relays indirect inhibitory feedback from AC to MGB. In this proposal, we outline a plan to answer three key questions related to selective filtering: Q1: Are selective spectral and temporal filtering evident in the auditory thalamus? Q2: How do thalamocortical interactions contribute to spectral and temporal filtering? Q3: How does attention modulate spectral and temporal filtering? The proposed experiments will lead to significant advances in our knowledge of the general mechanisms that underlie active sensory processing in all mammals, while also helping build toward a detailed understanding of the neural circuitry that allows humans to understand speech in noisy environments.
We are interested in how mutations that lead to human neurological disorders (particularly epilepsy) impact neuronal function. Much of our previous work has focused on how mutations change intrinsic neuronal excitability, but epilepsy is increasingly being associated with genes which are also predicted to perturb synaptic activity, and the aim of this project is to probe whether a subset of mutations linked to similar genetic epilepsy disorders have similar consequences for pre-synaptic properties. We will develop a lentiviral tool that will express a fluorescent protein (e.g. RFP) and a cDNA or shRNA to mimic a genetic disorder in a subset of cultured neurons. Recordings will be from untransduced post-synaptic cells, limiting the possibility of post-synaptic genetic effects contaminating readouts of the impact of mutations on synaptic release. We will also investigate whether incorporation of an activating opsin is sufficient for light based stimulation of the pre-synaptic neurons only. By incorporating cellspecific promoters, this project will also allow us to test the hypothesis that mutations that cause seizures have distinct effects in interneurons and excitatory neurons, including how they couple excitation to transmitter release. This project will dissect the synaptic mechanisms of disease, and correlate them with subsets of neurons.
The nervous system in maintained in a protective environment by a specialised vasculature. In contrast to the Blood Brain Barrier (BBB), the Blood Nerve Barrier (BNB) is poorly characterised despite having an important role in protecting peripheral nerves and its disruption being associated with neuropathies associated with pathologies such as diabetes and cancer. We have initiated a characterisation of the BNB in the sciatic nerve and have found that it is distinct from the BBB both in its permeability and cellular make-up. Moreover, we have developed a unique transgenic mouse in which ERK signalling in Schwann cells (SCs) in the nerve can reversibly open the barrier, which mimics the normal injury response. This provides a powerful model system for studying in a temporal manner how the BNB can be broken down and reformed. The aims of this proposal are threefold. 1. To characterise the nature of the BNB throughout the PNS and correlate differences with structural changes 2. To determine the role of SC-secreted Semaphorin 3A in the regulation of the BNB. 3. To analyse the expression and role of BBB transporters in the BNB.
The role of GABA and GABAA receptors in providing synaptic and tonic inhibition of neurons is an important aspect of normal brain function. This is evident when inhibition becomes dysfunctional, resulting in neurological and psychiatric diseases. GABA receptors are also subject to modulation by endogenous compounds. Paramount amongst these are the neurosteroids that regulate inhibition, but their physiological role and how they are involved in brain diseases is largely unexplored. Having discovered the binding site for neurosteroids on GABAA receptors, revealing a highly conserved site on receptor alpha subunits, we can now dissect both their physiological and pathophysiological roles by adopting a genetic-based approach. The main aim of this proposal is to characterise the GABA receptor alpha4 subunit in a mouse knock-in line that has been rendered insensitive to neurosteroids by mutation of its binding site. This subunit is involved in the assembly of extrasynaptic GABAA receptors. By investigating inhibitory transmission, using brain slice preparations and dissociated neuronal cell cultures, in conjunction with biochemical, chemical, electrophysiological, imaging (single particle tracking), pharmacological and molecular approaches, we will uncover the role(s) of neurosteroids at this highly sensitive extrasynaptic GABAA receptor that underpins tonic inhibition in the brain.
Nicotinic acetylcholine receptors (nAChRs) are major excitatory neurotransmitters and have been implicated in a number of neurological and psychiatric disorders. The primary aim of the project will be to combine synthetic organic chemistry and pharmacological techniques to examine allosteric modulation of nAChRs. This will build upon recent work in the Sheppard and Millar labs at UCL and will also exploit a refined homology model of the a7 nAChR that was generated as part of a rotation project during the first year of this PhD studentship. It is anticipated that the generation of novel compounds, combined with computer docking studies and molecular pharmacological techniques, will enable a greater insight to be gained into the mechanism of action of nAChR allosteric modulators.
Coordinated neural tube closure: The role of biomechanical properties in directing neuropore 30 Sep 2016
Neural tube (NT) closure is a morphogenetic event of vertebrate development that results in severe birth defects (e.g. spina bifida) when disturbed. The key genes/pathways of neurulation have been studied extensively, but many aspects of the developmental mechanisms remain unclear. This project addresses two questions: (i) how is neurulation linked mechanistically with the process of axial elongation, which accompanies spinal closure in higher vertebrates, and (ii) how/where do tissue-level biomechanical forces arise that drive NT morphogenesis? Neuro-mesodermal progenitors (NMPs) generate both neuroepithelium and mesoderm during axial elongation, and will be fate-mapped in the NT of cultured mouse embryos. Single-cell labelling by photo-conversion of cells expressing the Dendra2 construct will reveal the timing of neural commitment in NMPs. Requirement for NMPs in NT closure will be assessed in embryos mutant for Grhl3, a gene expressed in NMPs and where loss- or gain-of-function causes spina bifida. Biomechanical forces in the closing NT will be detected by electroporating a FRET-based mechanosensor that reports stress in cytoskeleton-linked proteins (e.g. alpha-actinin). Embryo manipulations (e.g. closed NT incision) will be tested for effects on FRET-reporter activity to identify the origin of closure forces, while mutant embryos developing spina bifida will be assessed for altered force distribution.
Life history of an organizer: what determins transient orgnaizer function in Hensen's node? 30 Sep 2016
The "primary organizer" of the vertebrate embryo is a group of cells at the gastrula stage which is able to induce a complete patterned nervous system when transplanted to another site. However, the position in the embryo where the organizer is located only has these properties for a short time. This time corresponds to when two particular populations of cells ("central epiblast" and "posterior deep") come together. After this, as cells leave to form the prechordal mesendoderm, organizer ability is lost again. The aim of this project is to find out whether the organizer function of Hensen's node is the sum of properties that exist in separate cell populations or whether new properties are generated by interactions between them, and thus determine how dynamics of these cells contribute to the transient nature of organizer function. Cell dynamics will be studied using carbocyanine dye (Dil and DiO) labelling of the 'central' and 'posterior' populations to identify their contributions and roles in the organizer. These populations, individually and combined, will be assessed by studying their transcriptomes by RNA sequencing. Their organizer function will then be assessed, in time-course, by the gene expression profiles in cells receiving signals from these populations