Prof T McKay
No more applications being accepted
Funded PhD Project (Students Worldwide)
About the Project
The molecular signature of age-related cognitive decline/dementia in cortical neurons includes alterations in inflammation, metabolism and autophagy. The scaffold protein p62 lies at the nexus of these events and we propose to dissect its specific roles in an established human cell model of neural ageing using state-of-the-art gene editing technologies.
Aims and objectives:
The accumulation of aberrant protein material in neurons is a hallmark of neuropathology in Parkinson’s disease (PD), Alzheimer’s disease (AD) and a range of childhood diseases, called lysosomal storage disorders (LSD). In inherited forms of PD, AD and all LSDs, the underlying gene defect is present in all cells of the body but most significantly affects neurons, or even subsets of neurons, within the central nervous system. It is intriguing why some cells are more susceptible to disease.
To date, virtually all therapeutic strategies for this spectrum of neurodegenerative disorders aim to break down and disperse this aberrant protein accumulation. We hypothesise that it is not the protein aggregates alone that are catastrophically toxic to neurons but the confused cellular messages that emanate from other cellular compartments, due to a defect in the processing of dysfunctional or unwanted protein.
Autophagy is a cellular process that breaks down ageing proteins and recycles the building blocks. The lysosome is the recycling centre where aberrant accumulation of proteins occurs in neurodegenerative diseases. We will search further upstream in the autophagy pipeline where a shunting effect occurs in diseased neurons. The focus of this investigation is a multifunctional protein called p62, involved in the early stages of aggregating and labeling aberrant proteins for autophagic processing. Intriguingly the p62 protein also contains motifs that orchestrate cellular messages involved in cellular metabolism, anti-oxidant and inflammatory responses. Regulation of these p62-specific responses is complex but they are cell type specific. As such, it is credible that deregulation of these signals could be the determinant cause of neuronal death and not the accumulation of aberrant protein per se. If our hypothesis is correct, we would be able to target therapies to disrupt these cell messages that could be applicable to a wide range of storage disorders. There are a vast number of drugs targeting such cell signaling pathways already approved by MHRA/FDA.
We have developed a team with unique but complementary skills and have access to vital patient biopsies, mouse models and state-of-the-art tools and technologies in order to carry out this investigation.
We currently have a repository of fibroblast cells from patients with 6 different LSDs and AD. We are able to employ genetic engineering technologies to reprogramme these cells to induced Pluripotent Stem Cells (iPSC) which can then be differentiated into neurons in the lab to study directly and compare the cell messages of patient and normal neurons.
Specifically the student will:
• Objective 1: Quantitate and compare the cell signaling activity LSD, AD and control iPSC-derived neurons to assign a disease state profile.
• Objective 2: Employ genome editing in patient iPSC to selectively delete functional regions of the p62 coding sequence and quantify changes to the disease state profile.
• Objective 3: Assess theco-localization of p62 protein with markers of cell signaling implicated in disease by Objectives 1 & 2) in histological brain sections from LSD and AD mouse models compared to age-matched controls, as well as comparing juvenile and aged brain sections.
• Objective 4: Evaluate the therapeutic potential of small molecule inhibitors of cell signaling networks shown to be deregulated in disease in in vitro models and by stereotactic injection in LSD mouse models.
Expected Outcomes: Elucidating the defined functional consequences of elevated p62 in neurological storage disorders would be a paradigm shift in developing treatment strategies resulting in improved understanding of disease mechanism and thus 4* REF-returnable publications. The potential for drug repurposing would expedite the route to clinic so this research could also represent a substantial REF Impact Study.
The supervisory team for this project will be Prof Tristan McKay, and Dr Fiona Wilkinson
The closing date for applications is 31st January 2017.
To apply, please use the form on our web page: http://www2.mmu.ac.uk/study/postgraduate/apply/postgraduate-research-course/ - please note, CVs alone will not be accepted.
For informal enquiries, please contact: [Email Address Removed]
Please quote the Project Reference in all correspondence.
Funding Notes
This scholarship is open to UK, EU and International students
For information on Project Applicant Requirements please visit: http://www2.mmu.ac.uk/research/research-study/scholarships/detail/vc-scieng-tm-2017-1-molecular-interrogation.php
References
Finally, the McKay lab have recently published two high impact papers describing the application of reporter gene constructs to measure the activity of precise cell signaling pathways including metabolism, anti-oxidant response and inflammation.