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Identification of novel cortical interneuron regulators implicated in neuropsychiatric disorders

   Cardiff School of Biosciences

  Prof Meng Li  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

Despite representing only ~20% of the entire neuronal population in the neocortex, the GABAergic (Gamma-Aminobutyric Acid) inhibitory interneurons play a pivotal role in most cortical functions. Dysfunction of these cells, which may arise from abnormal development, has been implicated in neuropsychiatric disorders such as autism, schizophrenia, and epilepsy. This has led to increasing interest in using stem cell derived interneurons as an experimental model to study disease aetiology as well as medicine per se in transplantation based cell therapy for epilepsy. Co-transplantation of interneurons with midbrain dopamine neurons and striatal medium spiny neurons are considered for cell therapy for Parkinson’s and Huntington’s disease, respectively.

However, our understanding of cortical interneuron development remains limited, which hinders the development of efficient protocols for their in vitro production from stem cells.

Through analysing our own RNAseq data, publicly available dataset on RNA and protein expression profile in the developing mouse and human medial ganglionic eminence (the birth place of cortical interneurons) and promoter binding sites on known key cortical interneuron transcription factors (eg. NKX2.1, LHX6/7/8 and DLXs), we have identified a short list of ~10 candidate genes that we predict to have a role in interneuron fate specification and/or differentiation. These candidates include transcription factors, signalling molecules and genes whose mutation is associated with increased risk to schizophrenia and autism.

Using CRISPR/Cas9 assisted genome editing technology, we have recently generated a human induced pluripotent stem cell reporter line (LHX6-GFP) that express GFP fluorescent protein hiPSC-derived cortical interneurons. We also generated a hiPSC line that carry a targeted insertion of dCAS9-KRAB in a safe harbor locus, a tool that allows inactivation of endogenous gene expression (CRISPRi) in hiPSCs and during neuronal differentiation. 

In this project we will employ these state-of-the-art experimental tools to functionally evaluate the selected candidates in promoting or suppressing interneuron fate decision and/or differentiation. The LHX6-GFP hESCs will be induced to neural stem cells along with or without lenti-viral based transgene expression of our candidates. The effect on interneuron programing will be measured by direct visualization of GFP expression by flow cytometry and other relevant assays. Candidates capable of inducing interneuron fate will be studied further for underlying molecular mechanisms, as well as in depth analysis of the induced neuronal cells.

The identification of novel interneuron regulators will not only advance our understanding of human neuronal development, but also offers improved methods for generating these clinically important nerve cells for therapeutics.

Experimental techniques to be learned and resources available during the project include (but not limited to):

- hESC culture and transgene expression

- In vitro differentiate of hESCs into cortical interneurons

- RNA and protein extraction

- Real Time PCR (qPCR)

- Western blotting

- Immunofluorescence

- Fluorescence microscopy and confocal microscopy

- Image J and Cell profiler for imaging analysis and quantification

- SPSS statistic

*Please note that this project can be completed as a PhD or MPhil)

Candidate requirements

A 1st or Upper 2nd class UK honours degree or equivalent. Please visit School of Biosciences Postgraduate Research for more details.

For those whose first language is not English, IELTS with an overall score of 6.5 with 5.5 in all subskills, or equivalent. Please see our English Language Requirements guidance for more details.

How to Apply 

To submit a formal application via Cardiff University’s online application service, click the 'Institution Website' button on this advert; in the ‘Apply’ box at the top-right of the page, select Qualification (Doctor of Philosophy/Master of Philosophy), Mode of Study (Full Time) and Start Date (this can be flexible as it is a self-funded project). This will take you to the application portal.

Candidates must submit the following:

 • Supporting statement

 • CV

 • Qualification certificates

 • Proof of English language (if applicable) 

In the research proposal section of the application, specify the project title and supervisors of the project. In the funding section, specify that you will be self-funding. If you are applying for more than one Cardiff University project with the same entry intake, please note this in the research proposal section as the form only allows you to enter one title.

Funding Notes

There is no funding attached to this project, so students will need to source their own (tuition, bench fees if applicable, living fees if applicable).

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