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SLC6A1 encodes GAT-1, a voltage-dependent gamma-aminobutyric acid (GABA) transporter that is responsible for the reuptake of GABA from the synapse. GABA is the primary neurotransmitter responsible for inhibiting neuronal activity in the brain, acting to balance out excitatory signals. Imbalance in this inhibitory mechanism can lead to the occurrence of seizures. SLC6A1-related neurodevelopmental disorder is a rare disorder, affects 1:50000 individuals. It is characterised by mild-to-severe developmental delay and/or intellectual disability, epilepsy and movement disorders. In this project, we will combine clinical knowledge of SLC6A1 with advanced human stem cell techniques to investigate how genetic variants in SLC6A1 cause altered neuronal development and activity. This will improve our understanding of certain neuronal disorders such as epilepsy.
We will use induced pluripotent stem cells (iPSCs) derived from three patients with different single point mutations in SLC6A1 to generate neurons and astrocytes in order to explore the dynamic interactions between them and how these interactions may contribute to the development of the disease. Additionally, we will employ SLC6A1 mutant lines to create 3D cell structures, known as organoids to mimics certain features of epileptic human brain. These organoids will be utilised to investigate neuronal excitability and network behaviours using patch-clamping and multielectrode arrays. We will perform proteomics and genetic screening to determine potential pathways to target to reverse aberrant neural functional behaviours of these models. The project promises to offer biological insight of pathogenic mechanisms and could pave the way towards identifying therapeutic strategies for patients with epilepsy.
Aim: To understand the molecular mechanism of aberrant neuronal functionalities in epileptic patient with SLC6A1 mutations
Objectives:
a) Identify the deregulated pathways in neurons derived from SLC6A1 patient iPSCs co-cultured with patients or healthy astrocytes
b) Identify the deregulated pathways in cerebral organoids derived from SLC6A1 patient iPSCs as compared to healthy organoids
c) Identify the functional abnormalities in the SLC6A1 patient’ models
d) identifying the function of possible therapeutic targets to rescue the abnormal functional behaviours of SLC6A1 models
Research training
This project represents a unique opportunity to gain in-depth training in neural stem cell. The appointed student will be trained in culturing human iPS cells and their differentiation into neurons and astrocytes as well as generating 3D cerebral organoid.
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
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 in the University. The appointed student will be part of the Faculty of Medical Sciences- Newcastle University. The successful candidate will join the research 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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