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  The role of the enzyme aconitase in epilepsy

   College of Health and Life Sciences

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  Dr Felix Chan, Dr Lissette Sanchez Aranguren, Prof G Woodhall  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

Epilepsy affects around an estimated 50 million people globally. It is the most common neurological disease; affecting people of all ages and walk of life. Despite many treatment options currently available for epilepsy, up to a third of all epilepsy patients still do not respond to treatments. These patients continue to live with severe uncontrollable epilepsy and are at risk of dying from their seizures. Thus, this highlights the need to identify new target for treatment development in epilepsy.

In this project, we will examine the role of the TCA cycle enzyme, aconitase, in epilepsy. My previous work has indicated that dysfunction of this enzyme; particularly in astrocyte; is important to drive epileptic activity (see Chan et al; Brain, 2019). Aconitase is an enzyme that catalyzes the reaction of citrate to isocitrate in the TCA cycle. This reaction is upstream of alpha-ketoglutarate, which is an important intermediary in glutamate and glutamine metabolism. In our previous work, we have shown that inhibition of aconitase led to depletion of glutamine in the tissue leading to mitochondrial epilepsy. However, aconitase exists in two form: cytosolic aconitase, encoded by the gene ACO1; or mitochondrial aconitase, encoded by the gene ACO2. It is unknown which form of aconitase contributes to epilepsy and understanding the contribution of each form would allow us to precisely target the right enzyme for therapeutic development.

We will use astrocyte culture (mouse and/or human) and conduct CRISPR-mediated gene knockout of Aco1 and Aco2. We will then characterise the effect of the loss of each subform of aconitase on: (1) astrocyte growth, development, and reactivity; (2) astrocyte glutamine metabolism and energetics; and (3) astrocyte physiology and impact on neurophysiology. Ultimately, we want to use these cell models for high-throughput screening of aconitase modulators to develop new treatment for metabolic epilepsy.

Estimated yearly cost of consumables

£10,000 per year

Person Specification

A Masters degree in a relevant subject with a 60% or higher weighted average, and/or a First or Upper Second Class Honours degree (or an equivalent qualification from an overseas institution)

Submitting an application

As part of the application, you will need to supply:

·        A copy of your current CV

·        Copies of your academic qualifications for your Bachelor degree, and Masters degree (if studied); this should include both certificates and transcripts, and must be translated in to English

·        A research proposal statement*

·        Two academic references

·        Proof of your English Language proficiency

Details of how to submit your application can be found here

*The application must be accompanied by a “research proposal” statement. An original proposal is not required as the initial scope of the project has been defined, candidates should take this opportunity to detail how their knowledge and experience will benefit the project and should also be accompanied by a brief review of relevant research literature.

Please include the supervisor’s name and project title in your Personal Statement.

If you require further information about the application process please contact the Postgraduate Admissions team at [Email Address Removed]

Biological Sciences (4) Medicine (26)

Funding Notes

There is no funding for this project.
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