PhD in Medicine: Characterising the interface between APOE and LOX in Alzheimer’s Disease

Outline

The presence of specific APOE alleles confer the highest risk of EOAD in humans, but the mechanisms involved are poorly understood. APOE is a lipid transport protein generated primarily in liver, but also astroglia and microglia. Here, we propose to characterise how the lipid regulatory roles of APOE interface with a key lipid metabolising protein, 12/15-lipoxygenase (LOX), itself already known to promote AD in mouse models of disease through unknown mechanisms.

Of relevance, LOX generates inflammatory biomolecules through oxidising lipids, termed eoxPL, discovered and characterised through our work in Cardiff.  Furthermore, LOX is expressed in neurones in human brain, although its role in normal brain function or disease is uncharacterised. Thus this project seeks to apply new findings in the area of lipid inflammation to the field of AD research.

In this project we will:

1. determine the effect of LOX deficiency on brain function in APOE-/- mice
2. determine the role of eoxPL (the new lipids from this pathway discovered in Cardiff) from LOX in regulating brain function in the context of APOE alterations.

Key tools we have available include:

1. mice lacking LOX, and double knockouts: LOX^-/-/ApoE^-/-
2. purified in-house generated LOX-derived eoxPL that are not commercially available
3. assays to detect these using high sensitivity using mass spectrometry in cells and tissues (Valerie O’Donnell lab).

We also have established multiple assays for cognitive function in mice including behavioural tests, methods for assessing neurotransmission and immunohistochemistry of brain structure (Mark Good lab).

What is funded

Full UK/EU tuition fees and a Doctoral stipend matching UK Research Council National Minimum.

Duration

3 Years

Eligibility

Open to all UK/EU students without further restrictions.

You will hold or expect to achieve a First or Upper Second Class degree in a relevant area (eg neuroscience, psychology, anatomy, physiology, natural sciences). As this is a training doctorate, previous research experience is not essential.