Visualizing alteration in mitochondrial structures in Brain astrocytes and neurones due to obesity and diabetes

About the Project

This project investigates a novel mechanism by which brain insulin resistance contributes to metabolic and cognitive dysfunction, focusing on the Nucleus of the Tractus Solitarius (NTS) within the dorsal vagal complex (DVC). While peripheral insulin resistance is well-characterized, the brain’s role in systemic metabolic regulation remains underexplored. Our research addresses this gap by examining how high-fat diet (HFD)-induced mitochondrial fragmentation in astrocytes and neurons disrupts insulin signaling in the DVC, leading to impaired glycemic control and increased food intake.

Preliminary findings reveal that in rodents, high-fat diet feeding and obesity lead to an increase in mitochondrial fragmentation in the nucleus of the solitary tract in the brainstem. This, triggers insulin resistance, hyperphagia, and elevated blood glucose levels. Additionally, we have demonstrated that increasing mitochondrial fragmentation in astrocytes alone is enough to induce insulin resistance, affecting both glycemia and feeding. Building on this, our specific objectives are:

1. Characterize mitochondrial structural changes in astrocytes and neurons within the NTS under conditions of obesity and diabetes, using correlative tomography and plasma FIB technology to achieve high-resolution visualization.
2. Determine whether fragmented mitochondria undergo mitophagy, using confocal imaging to assess degradation pathways and their role in cellular stress responses.
3. Investigate alterations in the extracellular matrix (ECM) triggered by mitochondrial fragmentation in astrocytes. We will use light sheet microscopy to visualize ECM remodeling, focusing on markers such as Aggrecan and Brevican, which are upregulated in response to mitochondrial stress.

Recent data from primary astrocyte cultures suggest that mitochondrial fragmentation increases the expression of ECM-associated proteins, potentially altering the extracellular environment and affecting neuronal communication. By integrating these findings, the project will provide insight into how mitochondrial dysfunction in glial cells contributes to broader neural and metabolic dysregulation.

The project’s novelty lies in its multi-modal approach, combining advanced imaging and molecular techniques to uncover the cellular and extracellular consequences of mitochondrial fragmentation.

Eligibility

Applicants to research degree programmes should normally have at least a first class or an upper second class British Bachelors Honours degree (or equivalent) in an appropriate discipline. A Master degree is desirable but not essential.

The minimum English language entry requirement for research postgraduate research study is an IELTS of 6.0 overall with at least 5.5 in each component (reading, writing, listening and speaking) or equivalent. The test must be dated within two years of the start date of the course in order to be valid. Some schools and faculties have a higher requirement.

How to Apply

To apply for this project applicants should complete an online application form and attach the following documentation to support their application.

• a full academic CV
• degree certificate and transcripts of marks
• Evidence that you meet the University's minimum English language requirements (if applicable).
• Evidence of funding

To help us identify that you are applying for this project please ensure you provide the following information on your application form;

• Select PhD in Biological Sciences as your programme of study
• Give the full project title and name the supervisors listed in this advert

Funding Notes

This project is open to applicants who have the funding to support their own studies or who have a sponsor who will cover these costs.