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Molecular Mechanisms of Trafficking and Signalling of TRPA1 Ion Channels

Primary Supervisor: Dr Xuming Zhang, College of Health & Life Sciences

Secondary supervisor:Professor Rhein Parri

PhD project title: Molecular Mechanisms of Trafficking and Signalling of TRPA1 Ion Channels

University of Registration: Aston University

Project outline:

Th transient receptor potential ankyrin 1 (TRPA1) is a nonselective cation ion channel broadly expressed in both neuronal and nonneuronal tissues. Residing on the cell membrane, TRPA1 is activated by a vast variety of harmful stimuli ranging from environmental irritants, pungent chemicals and endogenous metabolites to inflammatory agents. TRPA1 thus acts as a molecular sensor and sentinel of tissue damage, inflammation and oxidative stress, and has been implicated in numerous physiological processes and disease conditions such as thermo-sensation, pain, cancer, cardiovascular diseases and ischemia-reperfusion injury. During these conditions, TRPA1 activation is enhanced and contributes to various pathological processes. Once activated, TRPA1 triggers action potentials and release of neuropeptides from nerve terminals causing neuroinflammation. Meanwhile, activated TRPA1 further activates downstream intracellular signalling messengers, amplifying the effects mediated by TRPA1. Therefore, both activation and signalling of TRPA1 contribute to pathological processes in disease conditions.

We and others have found that enhanced TRPA1 activation is mainly due to increased trafficking of TRPA1 channels onto the cell membrane. However, the mechanisms of TRPA1 trafficking remain poorly understood. In this research, we aim to investigate the mechanisms responsible for increased trafficking and signalling of TRPA1 in physiological and pathological conditions. We will determine signalling messengers activated by TRPA1 and identify molecules mediating increased trafficking and signalling of TRPA1. We will then determine the functional consequences of increased TRPA1 trafficking and signalling. We will address these questions using a range of research skills including cell culture, molecular biology, cDNA cloning and manipulation, western blotting, Ca2+ imaging, immunocytochemistry, immunohistochemistry and cell biology assays.

You will be able to engage our cutting-edge research in two laboratories with complementary expertise, and will have excellent opportunities to learn multi-disciplinary knowledge (neuroscience, pharmacology and cell biology) and a range of interdisciplinary techniques in a vibrant and stimulating environment.

BBSRC Strategic Research Priority: Understanding the Rules of Life:Neuroscience and behaviour & Structural Biology

    Techniques that will be undertaken during the project:

    Cell line culture, DRG neuron isolation and culture, mammalian cell transfection, molecular biology techniques such as cDNA cloning and manipulation, site-directed mutagenesis, AAV-mediated gene transfer, western blotting, Ca2+ imaging, immunocytochemistry, immunohistochemistry and ELISA.

    Contact: Dr Xuming Zhang, Aston University