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Recipients:
University College London
University of Cambridge
Currency:
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Results

Studying murine behaviour and extending the hippocampal place cell model to 3 dimensions 27 Apr 2017

<p>In previous decades, studies focussing on hippocampal place cell activity have resorted to using 2-dimensional simulation models. I argue that such a paradigm proves to be insufficient when extending it to real-world, heavily 3D-biased, applications. As such, in this project, I propose an alternative approach to the study of place cells in which a rat&rsquo;s neuronal activity is wirelessly monitored while it is allowed to freely explore a lattice maze in all directions of Cartesian space. Most importantly, I aim to show that receptive fields are of similar sizes in the horizontal and vertical directions; I also hypothesise that concatenating receptive fields (RFs) from several place cells will yield a layered organisation with inter-RF distances being larger in the x-z/y-z planes than the x-y plane. Incidentally, this study will also provide data&nbsp;which I hypothesise will confirm the horizontal bias model in murine behaviour proposed by Jovalekic et al. (2011).</p>

Amount: £0
Funder: The Wellcome Trust
Recipient: University College London

Quantifying the activity of cis-regulatory sequences in the hypothalamus using single molecule fluorescence microscopy. 27 Apr 2017

<p>Every cell in the nervous system contains a programme of gene expression that not only determines its morphology and function, but also allows neurons and circuits to respond and adapt to sensory experiences. It is well document that changes in gene expression in response to these stimuli require cis-regulatory DNA sequences (enhancers), which mediate the activation and repression of specific genes. However, how a neuronal network as a whole tunes their transcriptional responses to achieve behavioural changes remain elusive. This project aims to address this by examining how the regulation of the genes arginine vasopressin (AVP) and oxytocin (OT) (neuropeptides that play a role in mammalian social behaviours) can differ between neurons and even gender, by identifying how different enhancer elements contribute to cell-type specific expression. To do this we will combine an enhancer assay with RNA single molecule fluorescence in situ microscopy (smFISH) in the hypothalamus, where these genes are primarily expressed. This will allow us to quantify the activity of specific enhancers in a given context, such as cell type and gender. The results will therefore give an indication of how information is encoded within these enhancer sequences that allows specific expression of the AVP and OT genes.</p>

Amount: £0
Funder: The Wellcome Trust
Recipient: University College London

Investigation of protein CoAlation in the process of apoptosis 27 Apr 2017

<p>CoAlation is a novel post-translational modification to proteins whereby Coenzyme A is covalently attached to proteins. It occurs as part of the oxidative stress response as an alternative mechanism to protein glutathionylation. It is specifically a modification of enzymes involved in cellular metabolism and protects catalytic thiol groups on active site cysteine residues from irreversible damage by reactive oxygen species and reactive nitrogen species.&nbsp;</p> <p>&nbsp;</p> <p>Applying oxidizing agents to cells results in induction of apoptosis. Such agents also induce protein CoAlation. The aims of this project are to monitor induction of apoptosis in HEK293 cells in response to treatment with oxidizing agents using anti-PARP3 and anti-Caspase 3 Western blot and Fluorescence-activated Cell Sorting and to analyse the pattern of CoAlation at different stages of apoptosis using anti-Coenzyme A Western blot.</p>

Amount: £0
Funder: The Wellcome Trust
Recipient: University College London

Developing gene therapy for the inherited childhood epilepsy, Dravet Syndrome 27 Apr 2017

<p>Dravet syndrome is a rare, incurable epilepsy which affects young children. Before two years of age they have seizures, incoordination and cognitive impairment. They carry mutations in the SCN1A gene, which codes for voltage-gated sodium channel Na<sub>V</sub>1.1. This protein is expressed in hippocampal inhibitory interneurons.</p> <p>&nbsp;</p> <p>Gene therapy offers several advantages over conventional drugs. It is a treatment which targets the cause of the disease by delivering the corrected copies of the SCN1A directly to brain cells.</p> <p>&nbsp;</p> <p>Our hypothesis is that we can incorporate a promoter to achieve persistent expression specifically in inhibitory interneurons of the hippocampus. We aim to compare two novel promoters against a pan-neuronal promoter, synapsin. The first is a truncated endogenous promoter, Gad67. The second is a synthetic promoter identified by <em>in silico</em> analysis.</p> <p>&nbsp;</p> <p>Before the&nbsp;project commences, we will clone these two promoters into lentiviral vectors. These, and a synapsin vector, will be injected intracranially into neonatal mice.&nbsp; At the start of the project the brains from four mice will be co-stained with antibodies directed against GFP and inhibitory interneurons to assess colocalisation. To measure persistence of expression from these promoters, the four remaining mice will be subject to whole-body bioluminescence imaging twice-weekly.</p>

Amount: £0
Funder: The Wellcome Trust
Recipient: University College London

Optimisation of carrier materials for the delivery of olfactory ensheathing cells in spinal cord injury 27 Apr 2017

<p>Transplant-mediated repair is a promising method in spinal cord injury (SCI) treatment. This&nbsp;involves transplanting therapeutic cells that promote nerve regeneration at the site of injury. For SCI, one promising&nbsp;therapeutic cell type is olfactory ensheathing cells (OECs). These&nbsp;have been shown to remyelinate demyelinated axons and promote new synapses following injury. They are also easily accessible clinically via trans-nasal endoscopic biopsy, and compelling pre-clinical evidence means that they are now close to being formally tested as part of a first-in-man clinical trial. However, currently these cells are delivered as a simple cell suspension, and&nbsp;this is unlikely to be optimal for creating a permissive and optimised&nbsp;repair environment.&nbsp;</p> <p>Thus, the objective of this project will be to develop and engineer optimised&nbsp;biomaterial scaffolds for OEC delivery.&nbsp;In&nbsp;doing so, it is hoped that a permissive 3D extracellular environment can be created, and the phenotype and behaviour of OECs&nbsp;optimised for spinal cord repair. Promising prospective biomaterials include fibrin, collagen and collagen-fibrin blends. To this end,&nbsp;we will investigate the effect of&nbsp;these&nbsp;promising carrier materials on&nbsp;OEC survival and phenotype, particularly with a focus on changes they may cause on 3D cell morphology.</p>

Amount: £0
Funder: The Wellcome Trust
Recipient: University College London

Developing a behavioural task for measuring the ability of listeners to perform auditory scene analysis. 27 Apr 2017

<p>The auditory brain separates simultaneous sounds arriving at the ear into identifiable and localisable sources by a process known as Auditory Scene Analysis (ASA). The two steps that are involved in ASA are i) segregation of the simultaneous auditory information and ii) the integration of the sounds from the same source into one stream. To understand how these two steps are connected and how different auditory cues interact to shape the scene, this project will develop a behavioural task and analyse the performance of human listeners. A target vowel will be presented alongside with a distractor vowel, and human listeners will identify what the target is. Listeners will only be able to identify the target if they can separate the two sounds: changing the location and pitch of target and distractor will help this. In order find out whether the separation of competing sounds is facilitated by the formation of perceptual streams, the vowels will also be presented as part of a sound sequence. Our hypothesis is that the ability to identify a target vowel will be improved by the formation of two perceptual streams. The long-term goal is to develop a behavioural paradigm suitable for humans and animals.</p>

Amount: £0
Funder: The Wellcome Trust
Recipient: University College London

Up and down regulation of MafB gene in the developing chick hindbrain. 27 Apr 2017

<p>The project's aim is to up and down regulate MafB gene, that is expressed in the Nucleus Laminaris (NL) and Nucleus Angularis (NA), in the&nbsp;developing&nbsp;chick hindbrain and ask questions about:</p> <p>1) formation of nucleus Laminaris&nbsp;and nucleus Angularis&nbsp;in the dorsal&nbsp;hindbrain;</p> <p>2) other effects&nbsp;on hindbrain development e.g interfering with fgf8 molecule expression, which in turn would affect the development of the cranial motor nerves VI, VII and nVIa.</p> <p>Such experimental techniques as <em>in </em><em>ovo</em>&nbsp;electroporation, immunofluorescence and <em>in situ</em> hybridization will be used to look at the genes expressed in the auditory brainstem.&nbsp;The<em> in </em><em>ovo</em><em> </em>electroporation&nbsp;constructs used will overexpress&nbsp;MafB and also express a dominant negative version of MafB and immunofluoresce&nbsp;analysis will be carried out to test whether the electroporation was successful. The <em>in situ </em>hybridization analysis will be performed to establish the effect of MafB on the expression of such genes like FGF8, Pou6F2, N-cadherin, gamma catenin, cadherin-13 and cadherin-22 in the hindbrain. These techniques would also allow the analysis of the formation of the nucleus Laminaris&nbsp;in the developing hindbrain.</p>

Amount: £0
Funder: The Wellcome Trust
Recipient: University College London

Developing an in vivo MT nucleation assay to investigate g-tubulin independent centrosomal MT nucleation 27 Apr 2017

<p>Centrosomes are major microtubule organising centres (MTOCs) in animal cells. During mitosis they recruit large numbers of gamma-tubulin ring complexes (g-TuRCs), which nucleate and anchor the microtubules required for spindle formation. Recent work in the Conduit lab has surprisingly shown that centrosomes lacking g-TuRCs can still organise microtubules. Nevertheless, it remains unclear if these microtubules are generated at centrosomes, or generated in the cytoplasm and then anchored at centrosomes.</p> <p>&nbsp;</p> <p>I aim to establish an <em>in vivo</em> microtubule nucleation assay to test these alternative possibilities. <em>Drosophila</em> larval brains, which are highly mitotically active, will be dissected from either wild-type flies or from mutant flies where the centrosomes lack g-TuRCs. They will be cooled on ice for 40 minutes in order to depolymerise all microtubules and then transferred to 25 degrees and chemically fixed at different timepoints. The brains will be stained for microtubules, centrosomes and mitotic DNA using antibodies already available in the Conduit lab and images will be taken on a confocal microscope. The location and intensity of new microtubule growth will be assessed. If the g-TuRC negative centrosomes do nucleate microtubules, the assay will be used to test candidate proteins for their role in centrosomal non-g-TuRC mediated microtubule nucleation.</p>

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Cambridge

Identifying Integrative and Conjugative Elements using DLIGHT 27 Apr 2017

<p>Integrative and conjugative elements (ICEs) are mobile genetic elements present in both gram-positive and gram-negative bacteria. They mostly reside in the host chromosome and under certain conditions, will excise and transfer to a new host via the conjugation machinery. ICEs have been found to provide the host with a wide range of phenotypes, including antibiotic and heavy metal resistance and the ability to colonise a eukaryotic host, promote virulence and biofilm formation. The ability of ICE to spread to different species of bacteria through horizontal gene transfer is a major factor in bacterial evolution. Bioinformatics approaches have been increasingly used to identify possible ICEs through sequence similarity. In this project, we aim to find out the effectiveness of using an algorithm, DLIGHT (Distance Likelihood based Inference of Genes Horizontally Transferred) that was originally used to detect lateral gene transfer, to identify integrative and conjugative elements. We will achieve this by assessing DLIGHT's ability to recover already documented ICEs. We will also use DLIGHT to test certain sequences which we suspect to contain ICEs. The predictions of new ICEs will then be vetted through manual analysis and collaboration with experimentalists.</p>

Amount: £0
Funder: The Wellcome Trust
Recipient: University College London

Investigating the sleep modulating effect of oxytocin in zebrafish models of autism. 27 Apr 2017

<p>In this project I will test the hypothesis that oxytocin expression and development of oxytocin-expressing neurons are altered in zebrafish with mutations in the ASD risk genes <em>cntnap2</em> and <em>chd8</em>. I hope to find evidence for the sleep modulating effects of oxytocin, and posit whether deficiencies in oxytocin signalling pathways may contribute to sleep disorders in autism mutants.</p> <p>I will examine oxytocin mRNA levels across the day/night cycle for both wild-type and mutant fish established in the Rihel lab. I will then analyse the pattern of oxytocin expression in the brains of mutant embryos and their wild-type siblings. From the findings in related studies with <em>cntnap2</em> mutant mice and the Rihel lab zebrafish models of autism (see references [3]<sup> </sup>and [6]), I expect to see an alteration in the amount of oxytocin mRNA for day/night between the wild-type and mutant embryos, and a change in the number of neurons expressing oxytocin. If such changes are found, they could explain the sleep phenotype observed in <em>cntnap2</em> autism mutants, and elucidate a link between neuronal circuit dysfunction and behavioural perturbation in this animal model.</p>

Amount: £0
Funder: The Wellcome Trust
Recipient: University College London

Evaluation of antimicrobial resistance and intrahospital transmission of respiratory pathogens in antibody-deficient patients. 27 Apr 2017

<p>I will be studying the respiratory microbiome of antibody-deficient patients to determine whether the number of bacterial species that are resistant to common antibiotics correlates with antibiotic usage, and whether transmission of these bacteria occurs between patients whilst attending hospital for immunoglobulin infusions. Immunocompromised patients provide a highly permissive environment for pathogen evolution as the lack of immune pressure allows resistance to develop without an associated fitness cost. Many of these patients take long-term prophylactic antibiotics together with frequent treatment courses, which we hypothesise acts as a selection pressure to further increase the number of resistant bacterial species in their microbiome. By analysing sputum samples with conventional microbiology techniques and MALDI-TOFF mass spectrometry, I will identify the bacterial species present in each sample and determine how many are resistant to common antibiotics, comparing this to questionnaires detailing the patients&rsquo; antibiotic usage. Additionally, for any resistant species identified in multiple patients, I will compare the antibiograms from each sample and extract DNA for 16S next generation sequencing to determine whether the presence of these species is due to intrahospital transmission. This project could inform clinical management of these patients as well as other situations where immunocompromised patients share hospital facilities.&nbsp;</p>

Amount: £0
Funder: The Wellcome Trust
Recipient: University College London

Pathways of nanopore assembly by bacterial toxins and immune effectors 27 Apr 2017

<p>To attack cells in our body, bacteria make use of toxins that drill holes in the cell membranes. Following a similar strategy, our immune system makes use of such pore forming proteins to target cancerous, virus-infected and bacterial cells. In the course of their action, pore forming proteins are first secreted as monomers, bind to the membrane, and next self-assemble into oligomeric pores.&nbsp;Some of the various open questions are how these pore assembly processes take place on more complicated, composite membranes such as bacterial envelopes. This project will aim to contribute to answering these questions, while providing the student research expertise in nanoscale microscopy methods&nbsp;applied to process that is essential for bacterial attack and immune defence.</p> <p>More precisely, the student will image live bacteria (E. coli) as they are attacked by the membrane attack complex. This is part of on-going atomic force microscopy experiments in the supervisors lab, which offer the possibility to visualise bacterial cell wall degradation in real time. Time permitting, the student will also be exposed to computational approaches to analyse such new data as well as past data on assembly and membrane insertion of immune effector perforin.</p> <p>&nbsp;</p> <p>&nbsp;</p>

Amount: £0
Funder: The Wellcome Trust
Recipient: University College London

An Investigation into the potential Th17 phenotype of ALCL 27 Apr 2017

<p>Anaplastic Large Cell Lymphoma (ALCL) is a paediatric T cell lymphoma whereby tumours have an 'activated' cell surface protein expression phenotype, defined by the presence of CD30. However, it has long been an enigma as to why these supposed &lsquo;transformed T cells&rsquo; do not express a T cell receptor (TCR) despite having the capacity to do so (as evidenced by the presence of molecular rearrangements of VDJ genes). The presumed cell of origin is a cytotoxic T cell as the large majority of tumours produce perforin and granzyme B yet in many cases expression of the helper T cell protein CD4 is also observed. We have refined the tumour cell phenotype to show expression of RORgt and production of cytokines including IL26, IL22 and IL17 hence suggestive of an origin in&nbsp;an innate lymphoid 3 cell&nbsp;(perhaps when the TCR is 'missing') or Th17 cells (when the TCR is expressed) that develop into tumours as a consequence of an inflammatory environment. Hence, the aim of this project is to establish this cellular phenotype and define the role of the (sometimes missing) TCR.&nbsp;</p> <p>&nbsp;</p>

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Cambridge

Dynamics of KLF17 expression in human naive pluripotent stem cells 27 Apr 2017

Conventional hPSCs represent a relatively late stage of embryonic development, termed the primed phase of pluripotency. Their use in research and medical applications is problematic because they display a differentiation bias and do not generate all cell lineages efficiently. The Smith laboratory has recently defined culture conditions that capture cells in an earlier phase, termed naïve pluripotency. Naive hPSCs have potential implications for more effective stem cell therapies because they don't display a differentiation bias. Very little is known about the genes that govern human naïve pluripotency in culture. The transcription factor KLF17, which is present in naïve hPSCs but absent in primed hPSCs, is of particular interest because it is specific to primates and not well studied. The key goal of this project is to generate a fluorescent reporter for KLF17. Alternative reporter designs will be trialled by fusing fluorescent proteins to either the start or the end of the endogenous KLF17 protein, in order to achieve optimal fidelity and sensitivity. The reporter(s) will then be exploited to monitor the dynamics of KLF17 expression in live cells both following withdrawal of factors to initiate differentiation, and also during the process of generating naïve cells by resetting.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Cambridge

Role of neuronal nitric oxide in the vasodilatory response to mental stress 27 Apr 2017

<p>Nitric oxide (NO) is a potent regulator of vascular tone. Until relatively recently, it was assumed that the isoform of NO synthase responsible for tonic NO release was <em>endothelial</em> nitric oxide synthase (eNOS). However, we now know that in humans, <em>neuronal</em> NOS (nNOS) is the primary NOS isoform responsible for regulating vascular tone <em>in vivo</em>. Neuronal NOS is also activated by mental stress and contributes directly to resistance vessel vasodilatation. However, our preliminary data indicate that this response is biphasic, suggesting a second mechanism underlying the vasodilatory response to stress. We hypothesise that this additional mechanism may be mediated through agonism of &beta;2 adrenoceptors. This hypothesis will be tested in healthy volunteers exposed to mental stress (Stroop test), using the gold-standard technique of venous occlusion plethysmography to measure forearm blood flow, coupled with intra-arterial infusions of selective inhibitors of nNOS and &beta;2 adrenoceptors. The key goals of this research are (i) to better define the regulation of vascular tone in healthy humans with a view to understanding potential mechanisms underlying vascular dysfunction in disease states; and (ii) gain a broader understanding of early experimental medicine approaches in the clinical setting.</p>

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Cambridge

Investigating the role of R2B receptor tyrosine phosphatases in developmental signalling pathways 27 Apr 2017

<p>Tyrosine phosphorylation is a key post translational modification that is often dysregulated in disease. The balanced actions of kinases and phosphatases are required for cellular homeostasis. However, the substrates and functions of phosphatases are poorly understood. The receptor tyrosine phosphatase PTPRK was identified as a recurrent fusion partner of the oncogene RSPO3 &ndash; an amplifier of the Wnt pathway. Additionally, PTPRK was identified in a forward genetic screen for modulators of APC min driven intestinal tumorigenesis. Given these genetic links, and hints in the literature that PTPRK can dephosphorylate beta catenin, a Wnt transcriptional activator, we plan to investigate the signalling cross-talk between PTPRK and Wnt signaling. First, this project aims to discover whether Wnt signalling influences the regulation of PTPRK at the messenger RNA and protein level. Second, we plan to test how depletion of PTPRK affects Wnt signaling output using luciferase reporter assays and western blotting. The outcome of this project will be a comprehensive assessment of the interplay between PTPRK and Wnt signalling, with important implications for the role of PTPRK in colorectal cancer, which is one of the current focusses of the Sharpe Lab.</p>

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Cambridge

Rate of degradation of Aurora kinases 27 Apr 2017

<p>Aurora kinases regulate&nbsp;the segregation of chromatids and are key enzymes in mitosis. AurA assembles the spindle poles; AurB faciliates cytokinesis of the daughter cells.&nbsp;Their ubiquitin-mediated degradation regulates the transition from mitosis back to interphase&nbsp;and show&nbsp;different kinetic profiles: AurA degrades 5-fold faster than AurB. Previous unpublished data from the Lindon lab showed that a&nbsp;AurA<sub>1-133</sub>-AurB<sub>78-345</sub> chimera tagged with GFP degraded with similar kinetics to full-length AurA. Therefore all of the information required for rapid degradation of AurA resides in the 1-133 region. We plan to construct various AurA-AurB chimeras&nbsp;and express them in dividing&nbsp;cells. We will carry out a quantitative analysis of degradation of these chimeras using single-cell fluorescence timelapse assays. We aim to identify the the minimal sequence within AurA<sub>1-133</sub>&nbsp;required to specify accelerated degradation kinetics. We plan to&nbsp;compare this&nbsp;with other known regulatory sequences for ubiquitin-mediated degradation ('degrons') and&nbsp;to gain a better understanding of how AurA engages the destruction machinery&nbsp;to affect&nbsp;its&nbsp;degradation kinetics. This information can assist the design of new therapeutic tools, such as PROTACs, that harness ubiquitin-mediated degradation to destroy targets not druggable by conventional means.</p>

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Cambridge

Microtubule organisation and role of LL5-beta in lymphoid stromal fibroblasts 27 Apr 2017

<p>The lymph node is a meeting point for lymphocytes with antigen-presenting cells, and rapidly expands during immune responses. Lymph node structure is highly compartmentalised, and the complex internal architecture is maintained during lymph node expansion. Therefore, mechanisms must exist to balance lymph node integrity with the need to remodel very rapidly. Fibroblastic reticular cells (FRCs) are the most abundant lymphoid stromal cell population, and span the full volume of the tissue. They provide structural support and are highly contractile. FRCs ensheathes bundles of extracellular matrix, termed the conduit, which filters draining lymph. The Acton lab works to understand how lymph nodes are remodeled during expansion and has shown that interaction between FRCs and dendritic cells change FRC behaviour. This project asks how the microtubule networks within FRCs are reorganised as the FRC network expands. Phosphoproteomic screening has revealed that LL5-beta, a protein targetting microtubules to adhesion sites is regulated by interactions between FRCs and dendritic cells. This may provide a mechanism by which FRCs uncouple from underlying matrix, and target secretion of proteases or new matrix to the expanding network. This project will investigate whether LL5-beta coordinates organization of microtubules in FRCs and whether dendritic cell contact changes LL5-beta activity.</p>

Amount: £0
Funder: The Wellcome Trust
Recipient: University College London

Generation and validation of chemosensitisation screens to identify genes interacting with an inhibitor of Menin, a protein with an established role in AML 27 Apr 2017

<p>Dr Vassiliou&rsquo;s team have recently used the <em>Streptococcus pyogenes</em>-derived type II CRISPR&ndash;Cas system to perform genome-wide drop-out screens in acute myeloid leukaemia (AML) cells. Some of the&nbsp; identified AML specific cell-essential genes are being pursued as potential therapeutic targets in AML.&nbsp;The team has adapted this system to perform &ldquo;chemosensitisation screens&rdquo; to identify genes whose inhibition collaborates with anti-leukaemic compounds to enhance leukaemia cell kill.</p> <p>I propose to&nbsp;perform&nbsp;chemosensitisation screens to identify genes interacting with an inhibitor of Menin, a protein with an established role in AML. By performing CRISPR-Cas knockout screens&nbsp;in the presence of a cytostatic or low cytotoxic drug doses, genes can be identified whose loss can synergise with the drug. Both resistance (enriched sgRNAs) and sensitization (depleted sgRNAs)&nbsp; genes can be identified by quantitative sequencing of the sgRNA cargo of cells in the presence and absence of the drug.&nbsp; Selected interactions can then be validated using targeted disruption of the targets with sgRNA, an approach that is well-established in the laboratory. Use of chemical inhibitors of target genes, together with the Menin inhibitor, can be used&nbsp;to validate the interaction pharmacologically.</p>

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Cambridge

Determining the Significance of Pathway Bias at the Calcitonin Gene-Related Peptide Receptor Family in Human Endothelial Cells 27 Apr 2017

<p>Family B G protein coupled receptors (GPCRs), notably the calcitonin like receptor (CLR), have been implicated in cardioprotective functions. The functional GPCR is a heterodimer of CLR and one of three possible receptor activity-modifying proteins (RAMPs). There are 3 main agonists for this GPCR: calcitonin gene-related peptide (CGRP), adrenomedullin (AM), and adrenomedullin 2 (AM2). CLR is pleotropic, activating intracellular pathways through coupling to G proteins or &beta;-arrestins. Indeed, we recently&nbsp;showed, using both a heterologous yeast expression system and mammalian (HEK-293) cell lines, that the signalling bias of the CLR is dependent upon both the agonist and the RAMP. However, the cell environment of the receptor massively affects signalling bias. Therefore, to validate these results, investigation of the pharmacology of the CLR in endogenous cell lines is essential.</p> <p>The aim of this research is therefore to use two different human cell lines (HUVECs and HUAECs) to pharmacologically investigate CLR/RAMP2 (the adrenomedullin receptor) and CLR/RAMP1 (the CGRP receptor) when endogenously expressed. It is hoped that this will provide greater insight into the function of CLR signalling in the vascular endothelium. This information may then be used to help characterise the pathophysiology of common cardiovascular diseases such as hypertension and myocardial infarction.</p>

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Cambridge