15 PhD Positions
are available within the
EU-funded Marie Skłodowska Curie Innovative Training Network on
NANOPARTICLE-BASED IMAGING AND THERAPY OF CHRONIC PAIN IN THE DORSAL ROOT GANGLIA (PIANO)
Chronic pain is a debilitating disease that affects approximately 1.5 billion people worldwide, and of those approximately 4% suffer from neuropathic pain. Neuropathic pain is often the result of nerve damage or a malfunctioning nervous system. It is described as a shooting or burning sensation that can come and then disappear, but it may also become chronic such that the pain becomes unrelenting and severe. Of equal note is the impact of chronic pain upon society as the costs related to disability allowance, treatment, lost wages and productivity impact the economy. Since current treatments for chronic pain are not entirely reliable, a better understanding of the mechanisms underlying chronic pain will provide new targets for analgesia.
The PIANO Network aims to develop tools to identify and visualise mechanisms of nociception in the dorsal root ganglia (DRG), outside the central nervous system (CNS). The DRG contain the cell bodies of specialised neurones that detect harmful stimuli in the periphery of the body and transmit noxious signalling to the spinal cord in the CNS.
We propose that local and targeted interventions at the level of the DRG will provide an opportunity to circumvent CNS-related side effects and optimise analgesic therapy. In models of neuropathic pain, we aim to identify the DRG involved in noxious signalling by visualising cells or molecules in the DRG which are directly or indirectly associated with the transmission of pain.
We will use novel methodologies based on nanoparticles targeted delivery to pain-related cells and molecules in the DRG. A good number of studies have shown a significant infiltration of macrophages into relevant DRG under neuropathic pain conditions. PIANO’s nanoparticles will be specifically designed to target the macrophages in the DRG, encapsulating both therapeutic payloads and imaging contrast reagents to monitor pain-driven activities.
To devise a state-of-the art approach for the visualisation of neuropathic pain/inflammation mechanisms in the DRG, and
To deliver analgesic molecules with the aid of nanoparticles.
JOB OFFERS DETAILS
We will provide a structured 3-year cutting-edge PhD training programme in and beyond the fields of neuropathic pain and its biological basis, biomaterials, chemistry, nanoparticles and imaging.
The earliest starting date will be March 2nd, 2021. The latest will be March 1st, 2022.
We are looking for highly motivated and talented PhD students holding a Master's degree or Bachelor's degree (UK) in scientific fields like biology, chemistry or physics. Excellent command of spoken and written English, communication skills as well as team spirit are essential. We are offering a competitive, interdisciplinary environment with a track record of intense mutual collaboration. In addition to the individual training-through-research our programme includes further elements such as workshops, summer schools, internships and secondments to the partners’ laboratories.
The following eligibility rules apply for participation in a Marie Skłodowska Curie Innovative Training Network:
Applicants must be in the first 4 years after obtaining their Master´s degree and/or Bachelor’s degree and must not have resided or carried out their main activity (work, studies, etc.) in the host country for more than 12 months in the 3 years immediately before the recruitment date. In addition, local regulations of the host countries may apply. The salary is based on standard living, mobility and family allowances which are adapted to the respective country of recruitment.
ESR 1 - The preparation, characterisation and testing of different biomaterials
- Host: UNIVERSITA' DEGLI STUDI DI CAMERINO (IT)
Supervisor: Piera Di Martino
Objectives: to prepare and test different nanoparticle technology formats for imaging, accommodating payloads, and specific targeting of pain-associated cells or molecules in DRG. We aim to control the particle size and drug content by taking four independent processing parameters and two characteristics of the material into account. The interdependencies between processing, material parameters, and the subsequent nanoparticle characteristics will be optimised to allow efficient production of drug-loaded polymer nanoparticles. This level of understanding should rapidly assist the project to have protocols for the production of optimal PLGA nanoparticles in place.
ESR 2 - Selection and production of the biomaterial format and then their functionalisation as nanoparticles
Host: ACADEMISCH ZIEKENHUIS LEIDEN (NL)
Supervisor: Luis Javier Cruz Ricondo
Objectives: to optimise the surface chemistry of the anoparticles so that they may be both functionalised to target macrophages and visible for molecular in vivo imaging. After the nanoparticles were prepared, the efficacy of the targeting nanoparticles towards macrophages will be tested and we will measure several characteristics by means of in vitro studies, in order to validate their function, stability, and specificity towards our target. After the nanoparticles are characterised for size and surface potential, we will determine whether enough contrast agent is loaded into the nanoparticles by measuring the NIRF signal with the Odyssey Clx infrared imaging system. Subsequently, we will test the uptake of the nanoparticles by macrophages by measuring the NIRF signal. We will administer different concentrations of nanoparticle on RAW 264.7 mouse macrophages for this experiment and confirm intracellular localisation of our nanoparticles by using confocal microscopy.
ESR 3 - Hydrogel patches for pain relief drug delivery
Host: POLYPURE AS (NO)
Supervisor: Erik Agner
Objectives: to develop hydrogel patches, where the addition of PEG to the nanoparticle surface, i.e. PEGylation, has the impact/effect to make biomaterials more compliant for in vivo use. Also, we will look to making a PEG hydrogel patch, which is robust enough for therapeutic use but at the same time, being biodegradable when disposed of.
ESR 4 - Neurosurgery and tissue co-culture maintenance of DRG and associated cells
Host: ACADEMISCH ZIEKENHUIS LEIDEN (NL)
Supervisor: Luis Javier Cruz Ricondo
Objectives: to isolate DRG neurons using a simplified protocol to facilitate rapid dissection of up to 40 individual DRG, complete within 20–30 min, followed by enzyme treatment or fixation. To support the project with provision of more tissues and cells, we will initiate DRG neurons to be used in creating an in vitro system. SCs, are important for their interactions with DRG neurons, where direct contact with DRG neurons provides additional stimuli sensed by specific membrane receptors, further improving the neuronal response. Furthermore, SCs release growth factors and proteins in the culture medium, which enhance neuron survival and stimulate growth and differentiation of neurites. However, SCs need a long time for proliferation, during which DRG neurons ultimately lose their function. The differentiation of ASCs into a SC-like phenotype provides a valid alternative to using SCs for the creation of an in vitro system, where we aim to initiate a SC-like ASC/DRG co-culture system. The present work will involve setting up of a protocol to harvest both DRG neurons and ASCs from adult rats. We will differentiate ASCs towards a SC phenotype and then combine the two cell types (DRG/ASC) in a direct co-culture system to investigate the interplay between neurons and SCs, which can then be used for downstream analyses, immunohistochemistry, and RNA profiling.
ESR 5 - Neuroregeneration and Neurotransplantation
Host: UNIVERSITA DEGLI STUDI DI CAMERINO (IT)
Supervisor: Piera Di Martino
Objectives: to develop genetic modification technology and tools (transgenic mice, knock-out mice, and replication-defective viral vectors) with the long-term goal to promote functional neuroregeneration of injured spinal cord tracts. Protocols will be developed where in vivo gene transfer technology is employed to modulate the response of neurons and glia cells to injury to provide new insights into the molecular and cellular mechanisms that promote and/or inhibit neuroregeneration.
ESR 6 - GABAergic signalling in peripheral sensory ganglia and its role in pain processing
Host: UNIVERSITY OF LEEDS (UK)
Supervisor: Nikita Gamper
Objectives: It has been shown that cell bodies of sensory neurons, including nociceptors, express multiple receptors for classical neurotransmitters, such as nAChRs, 5-HT3, glutamate, and GABA receptors. However, there is no coherent theory for why these receptors are present in sensory neuron somata, what are (if any) the sources of neurotransmitters that activate these receptors, and what physiological role the activation of these receptors may play in sensory signalling. The task of ESR6 is to establish which types of DRG neurons release GABA and which are responding to GABA release. The host lab has recently established that a subpopulation of DRG neurons is GABAergic and that ganglionic GABA release is analgesic. Sensory ganglia contain a heterogeneous population of neurons responding to various painful and non-painful stimuli. The PNS can alter information sent to the brain via a fully functional local GABAergic transmission system within the DRG, which is still poorly understood.
ESR7 - The gating mechanism of TRPV2: a quest towards effective modulators
Host: CHEM PRECISE (PT)
Supervisor: Filipa Cruz
Objectives: to develop a structure-based design of a new generation of transient-receptor potential vanilloid 2 channel (TRPV2) modulators for cancer therapy. Our recent biochemical, molecular biology and cryo-EM data show that piperlongumine is a reversible and allosteric antagonist for the TRPV2 channels with exquisite selectivity over a panel of TRPs (unpublished). By making the most of our acquired expertise and by taking into account the emergence of TRP channels as drug targets in cancer, we will conduct molecular dynamics simulations for the full-length channel over a microsecond timescale. Performing analyses of the obtained trajectories for the apo TRPV2, and liganded complexes (structures unpublished) will provide critical insights into pore dynamics. The design of potent TRPV2 modulators will be informed by the observed molecular recognition patterns. As a result, a focused library of piperlongumine and cannabidiol-inspired small molecules will be synthesized and profiled for TRPV2 inhibition through methods established in our laboratory and in the laboratories of PIANO members. The best candidates will be assessed for anti-proliferative activities against a range of disease-cell lines and xenograft mouse models of disease.
ESR 8 - The chemical modulation of in vivo macrophage functions at DRG sites
Host: THE UNIVERSITY OF EDINBURGH (UK)
Supervisor: Marc Vendrel
Objectives: to utilise the novel chemical tools from the EDIN group to examine macrophage activity as well as to modulate their function in vivo. M1 and M2 macrophages have distinct chemokine and chemokine receptor profiles, with M1 secreting the Th1 cell attracting chemokines CXCL9 and CXCL10 and M2 secreting CCL17, CCL22, and CCL24. Recently, it has been demonstrated in vitro that macrophages are capable of complete repolarisation from M2 to M1, and can reverse their polarisation depending on the chemokine environment (Davis MJ et al. 2013). The change in polarisation is rapid and involves rewiring of signalling networks at both the transcriptional and translational levels. A prodrug-fluorophore conjugate has been described which can deliver fluorescent and therapeutic loads into target cells with enhanced selectivity and reduced side effects. This is also the first chemical entity described that can monitor and modulate the function of M1macrophages in vivo. The structure carries a BODIPY scaffold, which is used by many groups as a fluorescent probe due to its excellent photophysical and cell permeability properties. Different prodrug-BODIPY combinations will be synthesised where the acidic pH in phagosomes would accelerate the cleavage of the N-acylhydrazone group to activate both fluorescent and functional responses in M1 macrophages. The specific release of BODIPY activatable fluorophores and cytotoxic drugs into M1 macrophages will be used to block the pro-inflammatory macrophage phenotype by means of ablation. The prodrug-BODIPY conjugates only target M1 macrophages with negligible effects on other macrophage subpopulations. The fluorescent BODIPY moiety will be used to visualise phagosomal acidification in macrophages in real time. A fluorescence analysis will be performed of M1 macrophages and the efficiency of cellular uptake of the conjugate and its intracellular activation upon phagosomal acidification.
ESR 9 - Thermo TRP ion channels as a key molecular and functional landmark for neuropathic pain transduction in subsets of somatosensory neurons
Host: UNIVERSIDAD MIGUEL HERNANDEZ DE ELCHE (ES)
Supervisor: Antonio Ferrer-Montiel
Objectives: to understand further the thermosensitive and analgesic interrelationship of thermo TRPs: TRPV1, TRPM8, and TRPA1 in neuropathic pain, and, secondly, to optimise novel biomaterials, in combination with encapsulated TRPV1 antagonists, for the modulation of neuropathic pain. Irritants such as hot peppers (capsaicin), mint, and mustard plants have served as powerful pharmacological tools for identifying molecules and mechanisms underlying nociceptive pathways showing that nociceptor subtypes can discriminate between noxious thermal, chemical and mechanical stimuli. These natural products have also revealed that thermo TRPs (TRPV1, TRPM8, and TRPA1) are involved in pain transduction by enhancing nociceptor excitability in pathological conditions. Studies have further shown that nociceptor subtypes can discriminate between noxious thermal, chemical, and mechanical stimuli. We plan to investigate the biophysical and pharmacological features of these channels to learn of the connection between thermos TRP channels, peripheral thermosensation, and thermoregulatory mechanisms. Furthermore, we recognise the importance of extracellular matrix components, such as hyaluronan, and by extension creating new biomaterials, in being able to modify these channels so that we have a stronger foundation to developing new classes of analgesic drugs.
ESR 10 - The synthesis of inhibitors that selectively target sodium ion channel subtypes
Host: UNIVERSITA’ DEGLI STUDI DEL PIEMONTE ORIENTALE AMEDEO AVOGADRO (IT)
Supervisor: Tracey Pirali
Objectives: to provide training in organic and medicinal chemistry for the design and synthesis of selective sodium ion channel blockers. Ion channels remain an undeniably valuable target but past attempts to expand the number of validated ion channel drug targets and create new drugs against these targets have mainly been disappointing. Many discovery efforts were stopped when molecules proved insufficiently selective for their intended targets and wound up causing severe side-effects in patients during early stage clinical trials. Historically, part of the problem has been because ion channels exist in different conformational states and designing appropriate platforms to support small molecule drug discovery has demanded a great deal of expertise. The recent efforts to identify selective sodium channel blockers were boosted by the discovery of subtype-selective sodium channel blockers, such as Nav1.3 and Nav1.72. Multicomponent reactions will be performed to synthesise compounds against these new targets.
ESR 11 - Development of MRI accessories for imaging and the physiological monitoring of pain
Host: MEDRES-MEDICAL RESEARCH GMBH (NL)
Supervisor: Stefan Wecker
Objectives: to produce MRI accessories to fit onto large company MRI instruments, e.g. Bruker and Siemens, for imaging and the physiological monitoring of pain. Firstly, this would include the task to custom design RF antennae (coils) for preclinical MRI experiments, made for all magnetic field strengths for animal imaging and in accordance with user specifications. Secondly, advances in MRI technology and analysis are revolutionising the way neuroinflammatory data may be interpreted during MRI studies. An advanced neurological analysis suite designed for optimal workflow and giving the output as single 2D and 3D displays, including combining anatomical images and results, such as DTI or perfusion colour maps, fibre tracks, and fMRI activations, will be provided. Thirdly, monopolar and bipolar probes, electrodes and stimulus-dissection instrumentation are to be provided for use with the MED neurophysiological monitoring system.
ESR 12 - Upconversion nanoparticles – a versatile solution to in vivo biological imaging of pain
Host: PERCUROS BV (NL)
Supervisor: Alan Chan
Objectives: to take UCNPs to beyond state-of-the-art by combining the advantages of upconversion luminescence and MRI to offer more imaging information for diagnosis and with much less toxicity. The integration of two molecular imaging techniques in such a structure will be utilised to imaging macrophage activity/inflammation. UCNPs doped with paramagnetic Gd3+ ions have attracted much attention as promising molecular imaging contrast agents because of the potential to reduce toxicity and enhance MRI performance. In MRI angiography and atherosclerotic plaque imaging, UCNPs containing Gd3+ have been studied where ultra-small NaGdF4 nanoparticles have proven more efficient than some commercial MRI contrast agents. Furthermore, they were shown to be rapidly excreted by the kidney (Xing et al., 2014). In another study, a chelating molecule [diethylenetriaminepentaacetic acid (DTPA)] was used to functionalise the surface of UCNPs with the aim of capturing potentially released Gd3+ ions, thus avoiding toxic effects in vivo (Xing et al., 2014). The size and morphology, fluorescence property, and colloidal stability of the UCNPs will be characterised by transmission electron microscopy (TEM) and DLS. The biocompatibility and biodistribution of the UCNPs will also be investigated.
ESR 13 - The use of exosomal cargo to investigate sensory neuron to macrophage communication after nerve trauma
Host: KING'S COLLEGE LONDON (UK)
Supervisor: Marzia Malcangio
Objectives: to test the hypothesis that the delivery of exosomes containing miR21 antagomir results in anti-nociceptive effects in models of neuropathic pain. Recently, the group of Malcangio reported a novel function of DRG perikaryal/neuron cell bodies, which were observed to release extracellular vesicles, including exosomes and miRNA upon activation/when active. Therefore, vesicles will be prepared, which will not cross the blood brain barrier, and they will be administered systemically at the time of nerve injury and 2 weeks after injury for prophylactic and therapeutic treatment, respectively. Mice will undergo pain behavioural tests and, at selected time points, the DRG will be examined immunohistochemically for markers of neuronal activation (p-ERK, CGRP). Macrophages will be isolated to determine their phenotype by flow cytometry analysis.
ESR 14 - Biomaterial based modulation of macrophage polarisation to induce anti-nociceptive effects during neuropathic pain
Host: PERCUROS BV (NL)
Supervisor: Alan Chan
Objectives: to assess the impact of different biomaterials and their surface chemistries on macrophage polarisation. It has recently been recognised that macrophages, besides being known for their phagocytic capabilities and immune defence, are also able to switch from a pro-inflammatory (M1) state into an anti-inflammatory (M2) phenotype. We will begin by analysing key cytokine/chemokine markers of macrophage polarisation and then test different nanomaterials for their ability to inducing the M2 phenotype from the M1 phenotype. The consequent cues that result from events related to biomaterial implantation, including pain relief, will be studied.
ESR 15 - Reversal of oxidative DNA damage by nanoparticle-based stimulation of DNA repair pathways to induce anti-nociceptive effects in models of neuropathic pain
Host: THE UNIVERSITY OF EDINBURGH (UK)
Supervisor: Marc Vendrel
Objectives: to look at specific inflammatory mediators and their impact on ROS and RNS to alter the excitability of sensory neurons during inflammation in animal models of chronic neuropathic pain. One important consequence of ROS/RNS production in sensory neurons is oxidative DNA damage. The post-translational modifications of proteins that contribute to the
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