Job Vacancies


The following table is showing all available positions. We intend to recruit all ESRs by July 2021. MSCA-ITN offers an attractive salary and working conditions. A unique feature of MSCA-ITN is that during the PhD research, ESR PhD students will be given the opportunity to perform at least two secondments of about 3 months each at the facilities of other consortium members. ESR PhD students will benefit from a dedicated training program in the various fields of expertise of the consortium partners. Salary is complemented with a mobility allowance.

If you want to apply for one of the position please read the basic eligibility criteria first and send your application to jobs@piano-diagnostic.eu providing all required information (incl. the ID of the position like "PIANO ESR ##" as reference).


Reference: ESR 1

Host: UCAM (UNIVERSITA DEGLI STUDI DI CAMERINO)
PhD enrolment.: UCAM (UNIVERSITA DEGLI STUDI DI CAMERINO)
Start: July 2021 earliest
Duration: 36 months

Workpackage: WP2.1
The preparation, characterisation and testing of different biomaterials

Task details:
Objectives: The task of ESR1 will be 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.

Expected Results: PLGA, which is already FDA approved, will be modified to produce optimal release kinetics of encapsulated payloads into DRG. The group will make structural changes, e.g. hydrophobicity, charge, biodegradation rate, and molecular weight, to make/produce/manufacture the optimal release formulation. We also expect to have drug-loaded PLGA nanoparticles by using two emulsification-solvent evaporation methods: homogenisation and sonication.

Planned secondments:
To LUMC for 2x2 months (m13-14 and m37-38) to learn about surface chemistry and targeting.
To PERC for 3 months (m25-27) to learn small animal imaging and to perform molecular imaging experiments.

To apply for ESR1 position, please submit your application at https://www.unicam.it/bandi/procedure-selettive-assegni-di-ricerca-2021-858356957 - deadline 28.06.2021 and send copy of the application to jobs@piano-diagnostic.eu


Reference: ESR 2 NOT AVAILABLE ANYMORE

Host: LUMC (ACADEMISCH ZIEKENHUIS LEIDEN)
PhD enrolment.: LUMC (ACADEMISCH ZIEKENHUIS LEIDEN)
Start: July 2021 earliest
Duration: 36 months

Workpackage: WP2.1
Selection and production of the biomaterial format and then their functionalisation as nanoparticles

Task details:
Objectives: The task of ESR2 will be 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.

Expected Results: PLGA nanoparticles harbouring PFC for 19F MRI will be developed together with also a NIRF dye, to enable visualisation of nanoparticles with NIRF spectroscopy for in vitro purposes. Peptides targeted to CD11b surface protein will also be conjugated to the nanoparticle surface.

Planned secondments:
To KCL for 2 months (m26-27) to learn about exosomes and extracellular vesicles as well as to share knowledge of such particles carrying payloads.
To CHEMFG for 2x2 months (m13-14 and m35-36) to learn about PEGylation and their impact upon the property, characteristics, and action of nanoparticles.


Reference: ESR 3 NOT AVAILABLE ANYMORE

Host: POLY (POLYPURE AS)
PhD enrolment.: LUMC (ACADEMISCH ZIEKENHUIS LEIDEN)
Start: July 2021 earliest
Duration: 36 months

Workpackage: WP2.1
Hydrogel patches for pain relief drug delivery

Task details:
Objectives: The task of ESR3 is 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.

Expected Results: PEGylated hydrogel patches will be produced using a proprietary purification technology called SDC, where it defines oligomer purity by monodispersity of the PEG. The use of monodispersed PEG and SDC purification technology results in exceptionally high-performance products. Our PEG hydrogel patches will be constructed to possess low swelling, tough mechanical properties, good adhesion and bactericidal activity. This patch will also be rendered more pliable with PLGA so that capsaicin may be used to remedy neuropathic pain.

Planned secondments:
To LUMC for 3 months (m25-27) to learn about the impact of PEGylated PLGA nanoparticles upon bioavailability and overall PK/PD and
2 months to TECO (m37-38) to learn about regulatory issues of PEGylated nanoparticles and delivery of payloads.


Reference: ESR 4 NOT AVAILABLE ANYMORE

Host: LUMC (ACADEMISCH ZIEKENHUIS LEIDEN)
PhD enrolment.: LUMC (ACADEMISCH ZIEKENHUIS LEIDEN)
Start: July 2021 earliest
Duration: 36 months

Workpackage: WP2.2
Neurosurgery and tissue co-culture maintenance of DRG and associated cells

Task details:
Objectives: The task of ESR4 is 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.

Expected Results: DRG neurons and ASCs combined to create an in vitro co-culture system facilitating the study of neuropathic pain and nerve regeneration.

Planned secondments:
To UCAM for 2 months (m13-14) to learn about nanomaterials and their chemical modification to make them functional.
To POLY for 2x2 months (m27-28 and m34-35) to learn about microscopy, Zeta potential measurements, DLS, and differential scanning calorimetry.


Reference: ESR 5

Host: UCAM (UNIVERSITA DEGLI STUDI DI CAMERINO)
PhD enrolment.: UCAM (UNIVERSITA DEGLI STUDI DI CAMERINO)
Start: July 2021 earliest
Duration: 36 months

Workpackage: WP2.2
Neuroregeneration and Neurotransplantation

Task details:
Objectives: The task of ESR5 is 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.

Expected Results: An understanding of the structural and functional aspects of nerve regeneration and plasticity in the injured and intact PNS in relation to pain. The focus will narrow in on the role of transcription, neurotrophic factors, and chemorepulsive proteins. These results will prove to be relevant in the context of neuropathic pain and in advancing our understanding of how neurons survive injury and how nerve cells form and maintain new functional connections after injury.

Planned secondments:
To EDIN for 6 months (m12-17) to learn about macrophages/inflammation imaging.
To UVA for 3 months (m31-33) to learn about nanoparticles and activatable probe design and to HMR for 2 months (m34-35).

To apply for ESR5 position, please submit your application at https://www.unicam.it/bandi/procedure-selettive-assegni-di-ricerca-2021-858356957 - deadline 28.06.2021 and send copy of the application to jobs@piano-diagnostic.eu


Reference: ESR 6

Host: LEEDS (UNIVERSITY OF LEEDS)
PhD enrolment.: LEEDS (UNIVERSITY OF LEEDS)
Start: July 2021 earliest
Duration: 36 months

Workpackage: WP2.4
GABAergic signalling in peripheral sensory ganglia and its role in pain processing

Task details:
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.

Expected progress beyond the state-of-the-art: Biochemical and molecular biology
approaches will be employed to understand the physiological role of GABA in this local signalling process, in particular, how the release of GABA in peripheral sensory ganglia can modulate transmission of pain-related signals from there to the CNS. Most importantly, focal application of GABA directly to DRG in vivo (as well as inhibition of reuptake of endogenous GABA or optogenetic/chemogenetic stimulation of endogenous GABA release) will be exploited to model acute and chronic pain. Recent data from the Gamper groups support the feasibility of the approach.

Planned secondments:
To UPO for 2 months (m25-26) to learn about small molecule libraries from UPO and how some of the compounds could impact GABA transmission.
To MED for 2x3 months (m13-15 and m35-37) to learn about monopolar and bipolar probes, electrodes, and stimulus-dissection instrumentation for neurophysiological monitoring.


Reference: ESR 7 NOT AVAILABLE ANYMORE

Host: CHEMFG (CHEMFG)
PhD enrolment.: FFUL (Faculdade de Farmácia da Universida)
Start: July 2021 earliest
Duration: 36 months

Workpackage: WP2.1
The gating mechanism of TRPV2: a quest towards effective modulators

Task details:
Objectives: The task of ESR7 is 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.

Expected Results: Generation of TRPV2 pore dynamics landscape; Synthesis of a range of NP-inspired molecules for screening in vitro and in vivo; Collection of cryo-EM TRPV2-ligand complex data.

Planned secondments:
To KCL for 2x3 months (m13-15, m34-36) to learn about the imaging of proteins that contribute to the excitability of sensory neurons and the consequential effect upon DNA damage.
To RECU for 3 months (mm25-27) to investigate the use of nanoparticles for optical in vivo imaging and cell-based assays.


Reference: ESR 8 NOT AVAILABLE ANYMORE

Host: EDIN (THE UNIVERSITY OF EDINBURGH)
PhD enrolment.: EDIN (THE UNIVERSITY OF EDINBURGH)
Start: July 2021 earliest
Duration: 36 months

Workpackage: WP2.3
The chemical modulation of in vivo macrophage functions at DRG sites

Task details:
Objectives: The task of ESR8 will be 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.

Expected Results: Different prodrug-fluorophore conjugates will be synthesised to discriminate closely related subpopulations of macrophages (i.e. pro-inflammatory M1 versus anti-inflammatory M2 macrophages). Whereas one part of this probe is the fluorophore for imaging, the other arm of the probe is the cytotoxic component used to deplete M1 macrophages in vivo without affecting other cell populations. It is now known that the M2 terminology encompasses a functionally diverse group of macrophages rather than a unique activation state. Profiling will be performed accordingly so that M2 macrophage subsets, and specifically M2a, M2b, M2c, and M2d based on their distinct gene expression profiles (Mantovani A et al. 2004, Rőszer T 2015), may be determined.

Planned secondments:
To LUMC for 2 months (m27-28) to learn to determine efficacy of the prodrug-fluorophore conjugate on macrophage subtypes.
To PERC for 4 months (m14-17) to learn about small animal pain models and co-culturing of DRG/ASCs and
HMR for 2 months (m30-31).


Reference: ESR 9 NOT AVAILABLE ANYMORE

Host: UMH (UNIVERSIDAD MIGUEL HERNANDEZ DE ELCHE)
PhD enrolment.: UMH (UNIVERSIDAD MIGUEL HERNANDEZ DE ELCHE)
Start: July 2021 earliest
Duration: 36 months

Workpackage: WP2.4
Thermo TRP ion channels as a key molecular and functional landmark for neuropathic pain transduction in subsets of somatosensory neurons

Task details:
Objectives: The aim of this PhD project is to understand the role of thermoTRP channels in nociceptor sensitization by chemotherapeutic drugs giving rise to chemotherapy-induced peripheral neuropathy (CIPN), and to use this information to validate therapeutic targets and discover candidate molecules for drug development. The successful applicant will use an in vitro model of CIPN to characterize the effect of the drugs in the electrogenesis of different subsets of sensory neurons and to develop therapeutic and/or bioimaging tools.

Hosting Institution: The Institute of Research, Development and Innovation on Healthcare Biotechnology of Elche (IDiBE) is located at the University Miguel Hernández in Elche campus. The mission and vision of IDiBE is to exploit a multidisciplinary program of translational science in the field of healthcare biotechnology with the commitment of transforming the generated basic knowledge into products and services for the benefit of society. The ultimate goal is to go “from the bench to the bedside” increasing the wealth by delivering the much-needed solutions to our society.

Sensory Neurobiology group: The sensory neurobiology group has more than 20 years research experience in the field of nociception and pain signaling, along with the validation and development of drug candidates. They are skilled in molecular and cellular biology, electrophysiology, imaging, in silico modelling and screening, molecular pharmacology and ion channels biophysics. The group has co-authored 140 papers and participated in more than 30 patent applications. Currently, the group has 3 compounds in phase II clinical trials and one in pre-clinical regulated studies. In addition, the group members have founded 4 spin-off/start-up companies.

Planned secondments:
To UPO for 3 months (m13-15) to learn about medicinal chemistry and
to POLY for 3 months (m26-28) to learn about biomaterial design.

Benefits: The successful candidate will be funded for 36 months with a competitive salary in accordance with the MSCA regulations for Early Stage Researchers. The salary includes a living allowance, a mobility allowance and a family allowance (if married).
The successful candidate will enroll in the PhD program on Molecular and Cellular Biology of IDiBE-UMH, getting the training provided by the MSCA-ITN and the doctoral program in terms of the training activities.

The successful candidate will have also to perform the secondments stablished in his/her personalized career development program.

Specific Requirements:
  • MSc in Biotechnology, Biology, Biochemistry, Pharmacy, Physics, Chemistry, Chemical Engineering or equivalent.
  • Experience on molecular and cell biology techniques.
  • Expertise on cell culture techniques.
  • Desirable expertise or knowledge in some of the following: experience in electrophysiology, calcium microfluorography, HTS screening and microfluidic technology

Send all the documentation by email to aferrer@umh.es and jobs@piano-diagnostic.eu with the subject ESR9.


Reference: ESR 10 NOT AVAILABLE ANYMORE

Host: UPO (UNIVERSITA DEGLI STUDI DEL PIEMONTE ORIENTALE AMEDEO AVOGADRO)
PhD enrolment.: UPO (UNIVERSITA DEGLI STUDI DEL PIEMONTE ORIENTALE AMEDEO AVOGADRO)
Start: July 2021 earliest
Duration: 36 months

Workpackage: WP2.4
The synthesis of inhibitors that selectively target sodium ion channel subtypes

Task details:
Objectives: Our objective for ESR10 is 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.

Expected Results: Multicomponent reactions will be performed to synthesise compounds for biological screening, followed by further modification to improve their potency. The synthesised analogues will be biologically evaluated and a number of hit compounds will be identified. Therapeutic efficacy will be tested on the different models from the other partners.

Planned secondments:
To UMH for 2x3 months (m13-15 and m35-37) to learn about another class of ion channels, the TRP ion channel family, and the small molecules from UMH/this group currently examined in clinical trials.
To TECO for 3 months (m25-27) to learn about biological assessment dossiers
with relevance for developing new strategies and solutions for the evaluation and implementation of a clinical translation approach for ion channel pain inhibition.


Reference: ESR 11 NOT AVAILABLE ANYMORE

Host: MED (MEDRES-MEDICAL RESEARCH GMBH)
PhD enrolment.: LUMC (ACADEMISCH ZIEKENHUIS LEIDEN)
Start: July 2021 earliest
Duration: 36 months

Workpackage: WP2.1
Development of MRI accessories for imaging and the physiological monitoring of pain

Task details:
Objectives: The task of ESR11 will be 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.

Expected Results: Innovative accessories from MED, including coils for 19F MRI and neurophysiological instrumentation and probes, will be used on this project. An advanced post-processing platform for pharmacokinetic modelling of DCE, perfusion-weighted
MRI datasets will be produced to provide intuitive visualisation of distinct regions on colour-coded maps and to allow extraction of perfusion parameters from DCE-MRI.

Planned secondments:
To LEEDS for 2x3 months (m13-15, m35-37) to learn about the GABAergic system in DRG in the context of pain research.
To RECU for 3 months (m25-27) to apply patch clamping and electrophysiology techniques.


Reference: ESR 12 NOT AVAILABLE ANYMORE

Host: PERC (PERCUROS BV)
PhD enrolment.: UVA (University of Amsterdam)
Start: July 2021 earliest
Duration: 36 months

Workpackage: WP2.1
Upconversion nanoparticles – a versatile solution to in vivo biological imaging of pain

Task details:
Objectives: The task of ESR12 will be 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.

Expected Results: Three different concentrations of Gd3+-ion-containing UCNPs will be synthesised: Non-Gd3+-integrated UCNPs, a low concentration of Gd3+-integrated UCNPs and a high concentration of Gd3+-integrated UCNPs in a high-boiling-point solvent mixture. The Gd3+ will be incorporated in the UCNP both as a dopant (internal) and as a surface ligand (external) so that we can demonstrate that simultaneous internal and external incorporation of Gd3+ ions can increase MRI sensitivity. This external Gd3+ ion attachment is expected to contribute further to the enhancement of MRI sensitivity.

Planned secondments:
To UVA for 2x2 months (m13-14, m37-38) to understand upconversion nanoparticle design and synthesis.
To POLY for 3 months (m25-27) to learn about lanthanide chemistry and probes.


Reference: ESR 13 NOT AVAILABLE ANYMORE

Host: KCL (KING'S COLLEGE LONDON UK)
PhD enrolment.: KCL (KING'S COLLEGE LONDON UK)
Supervisor: Marzia Malcangio
Start: July 2021 earliest
Duration: 36 months

Workpackage: WP2.3
The use of exosomal cargo to investigate sensory neuron to macrophage communication after nerve trauma

Task details:
Objectives: to test the hypothesis that the delivery of exosomes containing miR21 antagomir results in anti-nociceptive effects in models of neuropathic pain. Recently, we reported a novel function of DRG 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.

Expected Results: We expect to reduce neuropathic hypersensitivity of sensory neurons after nerve injury with an associated elevation of the M2 over the M1 phenotype after exosome delivery of miR21 antagomir.

Planned secondments:
To University Camerino (IT) and Medres Medical Research (NL).

To apply for ESR13 position, please submit your application at https://jobs.kcl.ac.uk/gb/en/job/018524/Early-Career-Researcher-Marie-Sklodowska-Curie and send copy of the application to jobs@piano-diagnostic.eu


Reference: ESR 14 NOT AVAILABLE ANYMORE

Host: PERC (PERCUROS BV)
PhD enrolment.: KCL (KING'S COLLEGE LONDON)
Start: July 2021 earliest
Duration: 36 months

Workpackage: WP2.3
Biomaterial based modulation of macrophage polarisation to induce anti-nociceptive effects during neuropathic pain

Task details:
Objectives: The task of ESR14 will be 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.

Expected Results: Macrophages exhibit remarkable plasticity in response to
environmental cues. In line with many other groups, we also expect to observe a spectrum of pro-inflammatory (M1) and anti-inflammatory (M2) macrophages together with/including many atypical M2 subtypes. Human monocytes will be cultured for 6 days on different biomaterials and we would expect to see some polarisation towards a M1-like phenotype, as evidenced by significantly higher expression of the pro-inflammatory transcription factors STAT1 and IRF5 as well as others exhibiting an M2-like phenotype with high expression of mannose receptor (MR) and production of the anti-inflammatory
cytokines IL-10 and CCL18.

Planned secondments:
To UCAM for 2x3 months (m25-27, m36-38) to learn about modulated response of neurons and glia cells by different genetic modification strategies.
To TECO for 3 months m13-15) to measure cytokine/chemokine markers of macrophage polarisation in response to biophysical and biochemical initiators.
To PROG for 2 months (m33-34) for exploitation of PERC results, data visualisation, paper and business plan writing.


Reference: ESR 15

Host: EDIN (THE UNIVERSITY OF EDINBURGH)
PhD enrolment.: EDIN (THE UNIVERSITY OF EDINBURGH)
Start: July 2021 earliest
Duration: 36 months

Workpackage: WP2.4
Reversal of oxidative DNA damage by nanoparticle-based stimulation of DNA repair pathways to induce anti-nociceptive effects in models of neuropathic pain

Task details:
Objectives: The task of ESR15 will be 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 excitability of sensory neurons and the consequential effect on DNA damage will also be studied.

Expected Results: This project will provide insights to the impact of ROS/RNS on DNA integrity in sensory neurons. Nanoparticle-encapsulated antioxidants will be synthesised to reverse the impact of ROS/RNS activity so that neuronal sensitivity may be reduced. Nanoparticle-based enhancement of DNA repair enzymes will be applied, and we expect these to reduce pain threshold and to maintain neuronal homeostasis by DNA repair and preserving its integrity.

Planned secondments:
To UMH for 2x3 months (m14-16, m37-39) to understand the role of TRP channels and their genes as part of the nociceptive circuitry that connects peripheral receptive fields to postsynaptic neurons in the spinal cord dorsal horn.
To PERC for 3 months (m27-29) to learn about peptide and nanoparticle preparations (solution, solid phase and combinatorial synthesis, orthogonal protecting techniques, and chemoselective methods).



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This project has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 956477.







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