Exploring tyrosine metabolism as a source of oxidative stress

Description

We are seeking a motivated researcher to work on a pioneering project investigating the role of oxidative stress associated with tyrosine metabolism.

Our cells are constantly exposed to stress in various forms. A major group of stressors is those that induce oxidative damage to cells and their constituents, including UV radiation from sunlight and environmental pollutants. The project will explore the novel idea that that molecules associated with the amino acid tyrosine are previously unrecognised sources of oxidative stress.

Dr Norman and colleagues have discovered that a specific breakdown product of tyrosine is a direct source of free radicals1. In patients with a genetic condition known as alkaptonuria (AKU) that causes lifelong exposure to this oxidative molecule, there is marked alteration to anti-oxidant pathways and greater incidence of devastating degenerative disorders including osteoarthritis and Parkinson’s disease2,3.

Phenylalanine-tyrosine metabolism is an essential biological pathway. This pathway is the major degradation route of the amino acids phenylalanine and tyrosine and the source of molecules with essential functions in multiple organ systems, including melanin, neurotransmitters such as dopamine, and thyroid hormones. Defining the contribution of this pathway to systemic oxidative damage will be a major breakthrough with potential to reveal new disease mechanisms and therapeutic targets.

You will help generate and characterize a novel mouse model through genetic deletion of HGD and NRF2; two key genes related to tyrosine metabolism and antioxidant pathways. In this opportunity, you will benefit from the Group’s long-standing expertise in tyrosine metabolism and access to world-class resources including advanced biochemical analytical techniques for metabolite and neurotransmitter analysis.

Objectives

Objective 1: To explore and develop key techniques for phenotypic assessment (analytical techniques including liquid chromatography mass spectrometry, mass spectrometry imaging, EPR spectroscopy and motor-cognitive assessment in mice)

Objective 2: To measure severity of oxidative disease in the HGD/NRF2 double knockout (DKO) compared to single-knockout and wild-type control mice. Phenotypes include the metabolome, brain pathology and central nervous system biochemistry.

Novelty

Your research will provide the first systematic exploration of oxidative stress in experimental models of tyrosine metabolic dysregulation. You will break new ground by being the first to:

• Study brain pathology across the lifespan in multiple mouse models of target diseases
• Explore potential interaction between oxidative tyrosine metabolites and pathways with an established role in oxidative stress (NRF2)

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 neurological phenotype in this new model. You will gain experience with a range of widely-applicable and cutting-edge techniques: in vivo experimentation, tissue collection, mass spectrometry brain tissue imaging4, histological analysis of tissue phenotypes, immunohistochemistry for specific proteins and signalling pathways, and metabolomics (metabolites and neurotransmitters)2.

Potential impact

• Inform new treatment approaches in multiple diseases including chronic ageing-related disorders
• Securing of further funds – broadened appeal through relevance to common chronic diseases, partnership with Royal Liverpool University Hospital will maximise clinical potential of research