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Enteric Nervous System dysfunction in Alzheimer’s disease


Project Description

Hypothesis: Alzheimer’s disease will alter the function of the enteric nervous system, echoing those changes seen in the brain.

Our aim is to comprehensively study the impact of AD on the morphology and function of the gut. We will identify how EGCs and neuronal signalling in the ENS are altered as a result of AD and determine the impact AD has on gut permeability and barrier function. In the latter stages of the project we will translate our scientific discoveries from animal models to humans.

Methodology and Innovations

OBJECTIVE 1: Study the effect of AD on EGCs
a. Morphological investigations will include immunohistochemical staining of EGCs of the GI tract in situ, dual fluorescence labelling and state-of the-art 3D glial morphometric quantification, pioneered by VJ.
b. Isolation and culture of EGCs using immunopanning – the first time such a technique will be applied to the ENS field (VJ) – INNOVATION
c. Functional analyses including secretome profiling to establish reactivity and inflammatory marker release (VJ, SC), and Ca2+ imaging studies (at ACN; AV)

OBJECTIVE 2: Measure neuronal signalling from the gut
a. Co-culture of ENS neurones and ECGs to establish non-cell autonomous effects of AD EGCs on neurone growth (axon chambers), survival and synaptic function (staining for synaptic punctae, baseline release of neurotransmitters) (VJ, DD)
b. The effect of AD on afferent transmission from the gut will be explored by extracellular afferent nerve recordings from the small and large intestine and motility studies to investigate enteric neural circuits (DD)

OBJECTIVE 3: Identify alterations in gut barrier permeability
a. Intact gut epithelial barrier will be modelled using a Caco-2 epithelial monolayer in vitro. Permeability will be measured in the presence of AD or control EGCs or conditioned media by way of a fluorescence permeability assay and trans-epithelial electrical resistance (VJ, DD)

OBJECTIVE 4: Translate to man
b. Translate our findings from animal models to human AD using donor tissues from cancer resection (healthy margins, SK, VJ, DD).

Applications

Applicants must apply using the online form on the University Alliance website at https://unialliance.ac.uk/dta/cofund/how-to-apply/. Full details of the programme, eligibility details and a list of available research projects can be seen at https://unialliance.ac.uk/dta/cofund/

The final deadline for application is 12 April 2019.

Funding Notes

DTA3/COFUND participants will be employed for 36 months with a minimum salary of (approximately) £20,989 per annum. Tuition fees will waived for DTA3/COFUND participants who will also be able to access an annual DTA elective bursary to enable attendance at DTA training events and interact with colleagues across the Doctoral Training Alliance(s).

This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 801604.

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