利物浦大学招收细胞生物学博士
About the Project
We are seeking a motivated researcher to work on a pioneering project investigating the role of oxidative stress in alkaptonuria (AKU) and associated conditions.
AKU is a rare disorder of metabolism caused by congenital deficiency in the enzyme homogentisate 1,2-dioxygenase (HGD), resulting in increased circulating concentrations of homogentisic acid (HGA). Over many years HGA is deposited in connective tissues throughout the body as a dark pigment, which is central to the devastating multiple organ pathology observed in AKU including severe early-onset osteoarthropathy and cardiac disease.
There is growing evidence that oxidative stress is a major part of AKU disease pathophysiology. The Liverpool AKU Research Group has shown that HGA is redox-active, that pigment derived from HGA is a direct source of free-radicals and that anti-oxidant pathways are markedly altered in AKU biofluids and tissues. Oxidative stress associated with lifelong exposure to HGA is thought to account for a number of co-morbidities in AKU, including common diseases such as osteoarthritis, Parkinson’s disease and cataracts; these diseases have markedly increased prevalence in AKU compared with the general population.
This project will explore the potential role of NRF2, a major antioxidant regulator, in AKU and associated conditions. NRF2 is shown to be a key mediator of oxidative stress in common osteoarthritis and is identified as a treatment target in numerous common diseases. Mouse models of AKU have been developed in which the gene for HGD is deleted and is able to reproduce most of the AKU phenotypes, including elevated plasma HGA and joint pigmentation, but not the major degenerative changes to multiple organ systems observed in human AKU.
You will help generate and characterize a novel mouse model through genetic deletion of HGD and NRF2; two key genes related to AKU and antioxidant pathways. This innovative model presents new opportunities to uncover disease mechanisms and therapeutic targets. The study of lifelong exposure to specific oxidative metabolites in this model has potential to uncover the involvement of these molecules in the pathology of more common degenerative diseases including osteoarthritis and Parkinson’s disease.
OBJECTIVES
Objective 1: To measure severity of AKU phenotypes in the new AKU model with HGD/NRF2 double KO (DKO) compared to HGD KO mice. Phenotypes include brain and joint pathology, HGA/HGA-derived pigment accumulation, the metabolome and central nervous system biochemistry.
Objective 2: To assess the effects of applied mechanical joint loading in vivo on OA development in HGD/NRF2 DKO. This will test whether the combination of the DKO and joint trauma can better reproduce AKU joint phenotypes.
Objective 3: To test the efficacy of nitisinone treatment on disease severity in this new model of AKU.
NOVELTY
Your research will provide the first systematic exploration of oxidative stress in AKU experimental models. You will break new ground by being the first to:
• Study brain pathology across the lifespan in AKU
• Perform joint loading experiments to understand the skeletal phenotype and severe osteoarthritis development
• Assess extracellular and cellular mechanisms as potential novel treatment approaches
EXPERIMENTAL APPROACH
Generation and characterisation of a new DKO mouse model of AKU, in which two current mouse lines will be crossed (underway). The main focus for this proposal is characterisation of the skeletal (OA development) and brain phenotypes compared to the AKU phenotype.
You will gain experience with a range of widely-applicable and cutting edge techniques: in vivo experimentation, tissue collection, mass spectrometry brain tissue imaging, micro-CT and histological analysis of tissue phenotypes, immunohistochemistry for specific proteins and signalling pathways, and metabolomics (metabolites and neurotransmitters).
POTENTIAL IMPACT
• Inform new treatments in multiple diseases including OA as a common chronic ageing-related disease, which is currently not treatable (except for pain and end-stage joint replacement).
• Securing of further funds – broadened appeal through relevance to common chronic diseases, clinical links through partnership with Royal Liverpool University Hospital will maximise clinical potential of research
APPLICATION PROCESS
Please email your CV and cover letter to Dr Poulet: b.poulet@liverpool.ac.uk
• Please note: Applications will close as soon as a suitable candidate is found. The listed deadline may therefore be subject to change.
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