Parkinson's disease (PD) is a chronic, progressive neurodegenerative disease characterized by loss of nigrostriatal dopaminergic pathways. It affects 0.3% of the population. The main symptoms observed in PD are tremor, rigidity and bradykinesia. In addition to several non-motor symptoms such as sensory disturbances. Among the sensory symptoms, pain is observed in approximately 30–50% of PD patients. The advent of individual patient-derived human-induced pluripotent stem cells (hiPSCs), combined with the ability to generate various types of neuronal and glial cell type, holds great potential for understanding the mechanisms of various neurodegenerative disorders. This PhD project in research group of Dr Mouhamed Alsaqati will focus on understanding the molecular mechanism underlying the chronic pain observed in the majority of Parkinson’s patients, and proposing some pharmacological interventions that may be used to mitigate the pain in those patients.
Mitochondrial dysfunction and α-synuclein aggregation play major roles in the pathogenesis of PD. Mutations of the mitochondrial PTEN (phosphatase and tensin homologue)-induced kinase1 (PINK1) are important causes of Parkinson disease (PD). In this study we will employ two models for Parkinson's; PD patient iPSCs carrying a triplication of the alpha-synuclein gene, resulting in 4 copies of SNCA, and PINK1 knockout hiPSCs. We will generate a PINK1 stable knockout hiPSCs using CRISPR interference (CRISPRi), which is a fast and accurate method to edit genomic DNA. Sensory neurons derived from PD patient model and the CRISPRi PINK1 edited hiPSCs will be utilised to understand the abnormal pain pathology in Parkinson's patients and develop some pharmacological targets to reverse the aberrant neural functional behaviours of these neurons. The project promises to offer biological insight of pathogenic mechanisms and could pave the way towards personalized medicine for chronic pain in Parkinson's patients.
Hypothesis: Sensory neurons derived from PD patient models exhibit abnormal spontaneous functional behaviour and aberrant response to pain stimuli.
Aims and objectives
Aim: To understand the molecular mechanism of chronic pain in patient of Parkinson’s disease
Objectives: We will
a) Identify the deregulated pain pathways in sensory neurons derived from PD patients
b) Identify the deregulated pain pathways in sensory neurons derived from human iPSCs with PINK1 CRISPR knockout model
c) Identify the functional abnormalities in the PD patients’ models
d) identifying the function of possible therapeutic targets to rescue the abnormal functional behaviours of Parkinson’s sensory neurons
Research training
This project represents a unique opportunity to gain in-depth training in neural stem cell and peripheral nervous system. The appointed student will be trained in culturing human iPS cells and their differentiation into sensory neurons containing nociceptors, proprioceptors and mechanoreceptors.
Techniques to be used:
A variety of cellular, genetics, molecular and functional techniques will be combined, including
· Cell biology; imaging, Western blotting
· Genetics; PCR and RT-qPCR, cloning
· Functional Assays; calcium imaging, Patch-clamp and Multi-electrode arrays
· Advanced molecular biology techniques; RNA Seq, CRISPR-Cas9 technology
Generic skills training is offered through the Newcastle University learning HUB. As well as the specific training detailed above, students will have access to a wide range of seminars and training opportunities at the University. The appointed student will be part of the Faculty of Medical Sciences- Newcastle University. The successful candidate will join a vibrant Pain Group at Newcastle University which includes academics and students from pharmacy, dentistry, neuroscience and psychology and they will have opportunities to interact and work with our industry partner/s. Applicant should hold or expect to hold a 2:1 or 1st class degree.
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