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PhD Scholarship project 2

SBBS Research Scholarships 2022: Project 2

Understanding post-transcriptional regulatory mechanisms important for  chronic pain

PI: Dr Olga Baron

Applications are invited from highly-motivated and independent individuals to join the group of Dr. Olga Baron at the Conway Institute, University College Dublin. We use Drosophila and mouse genetics to understand molecular mechanisms important for sensitisation of nociceptive (pain sensing) circuits in the context of chronic pain. As a basic mechanism of escaping threat, pain is generally a valuable commodity; however, can be harmful and debilitating if excessive and chronic. The Global Burden of Disease Study finds chronic pain conditions - such as musculoskeletal disorders - as the leading cause of disability worldwide. Therefore, there is a great need in research aiming at identifying novel effective druggable mechanisms and molecular targets. Our data suggests that nucleo-cytoplasmic balance of the RNA binding protein (RBP) - Rbfox1/A2bp1 - is a stress-response mechanism in neurons that is important for regulating normal nociception. Risk allele in Rbfox1 was found to be associated with osteoarthritis, which is a musculoskeletal condition most commonly causing chronic pain in patients. The successful PhD candidate will be investigating the putative target genes downstream of Rbfox1 and the nature of their regulation trough specific targeting of nociceptive neurons using molecular biological, biochemical and behavioural approaches.

Pain in musculoskeletal disorders such as osteoarthritis is a major debilitating symptom, and the main reason for why patients seek medical attention and intervention. Current therapeutic strategies provide only poor analgesic control, often involve major surgery and can have significant and very serious side effects, such as myocardial infarction (NSAIDs) and addiction (opioids). The key drivers of persistent pain in OA is believed to be both hypersensitivity of peripheral nervous system as well as pain sensitisation via central mechanisms. A better understanding of the molecular mechanisms that drive the altered function of nociceptive circuits is therefore urgently needed, especially to improve targeted drug development.

We are interested in the role of the RNA binding protein Rbfox1/A2pb1 in mediating maladaptive plasticity of peripheral nociceptors in chronic pain conditions. Genome wide association studies (GWAS) studies have linked a risk variant in the Rbfox1 gene to hand osteoarthritis in a UK Twin study and an independent Finish female cohort. As an alternative splicing factor, Rbfox1 influences an extensive gene regulatory network, favouring expression of specific isoforms of molecules that are important for neuronal excitability and activity. Indeed, it is thought that Rbfox1 is central to regulating the balance and adaptation of neuronal circuit to activity changes. Our data suggests that nucleo-cytoplasmic balance of the RNA binding protein (RBP) - Rbfox1/A2bp1 - is a stress-response mechanism in neurons that is important for regulating normal nociception.

In this PhD project you will work with Dr Olga Baron at University College Dublin. You will use the fruit fly - Drosophila melanogaster to study genes that are regulated by fly orthologue Rbfox in nociceptors specifically. This will involve innovative high-throughput behavioural assays that will enable us to understand if manipulation of those genes may ameliorate nociceptive hypersensitivity phenotypes in the fly. In parallel, you will analyse the mRNA expression and regulation of alternative splicing regulation of those candidate genes in mouse tissue isolated from after sensory neuron specific conditional Rbfox1 knock-down. The overall aim is to use these insights in order to develop novel molecular sensor tools that may be applied in fruit flies and in vitro systems for small molecule compound development and testing.

Your profile:

  • BSc (Hons) or MSc in genetics, cell biology or neuroscience (Minimum grade of 2.1)
  • Enthusiastic to study mechanisms of signalling and regulation of gene expression in the nervous system
  • Ability to drive the project with a high degree ofindependence
  • Excellent organizational and interpersonal skills with ability to manage multiple tasks independently as well as in close collaboration with others
  • Highly motivated, a quick learner and very enthusiastic about working with genetic animal models
  • Experience with model organisms (e.g. Drosophila, mouse), imaging techniques, and knowledge of bio-informatics tools are welcome
  • EU applicants only

The position is available from 1st of September 2022 fully funded by UCD School of Biomolecular and Biomedical Sciences (SBBS) with following conditions:

➢ Full EU fees + €18,000 per annum stipend over four years.
➢ Each student will be enrolled in a Structured PhD programme, associated with SBBS.

➢ Each student is required to demonstrate in appropriate laboratory practicals as part of their funded scholarship. Demonstrating hours and lab practicals are detailed and assigned by the SBBS Demonstrating Committee. (For more information:
https://www.ucd.ie/sbbs/study/researchprogrammes/)

For informal inquiries please contact: olga.baron@ucd.ie
 

Applications: Please email your motivation letter, CV (including grades) and contact details of 3 references to:
olga.baron@ucd.ie

Application deadline: July, 28th, 2022

 

Contact the UCD School of Biomolecular and Biomedical Science

H1.38 O’Brien Centre for Science, University College Dublin, Belfield, Dublin 4, Ireland.
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