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Dr P Teismann, Prof J Forrester
No more applications being accepted
Competition Funded PhD Project (European/UK Students Only)
About the Project
Supervisors: Dr Peter Teismann, Prof John Forrester, Prof Gernot Riedel, Dr Iain Greig & Dr Laurent Trembleau
Parkinson's disease (PD) is a neurodegenerative disorder that affects more than 10,000 people each year in the UK. One of the biggest challenges in providing treatment is our current lack of knowledge concerning disease development. PD is caused by the death of brain cells in the substantia nigra, but we understand very little of the mechanisms involved. We have recently identified a key role for a protein called HMGB1, which is released when cells die and plays a major role in inflammation. HMGB1 can trigger different cellular pathways all leading to the death of brain cells. We have already demonstrated that inhibition of HMGB1 by a specific antibody and by the liquorice root-derived compound glycyrrhizin, an inhibitor of HMGB1, leads to neuroprotection. Here we propose:
(a) to confirm HMGB1 as the main target for glycyrrhizin,
(b) assess the main structure responsible for HMGB1 inhibition,
(c) generate new compounds based on molecular modelling and
(d) assess these novel compounds in models of PD. Taken together we present a comprehensive study to investigate HMGB1 as a brand new target for a neuroprotective agent, which could revolutionize the treatment of Parkinson’s disease, and potentially other neurodegenerative diseases.
Parkinson's disease (PD) is a neurodegenerative disorder that affects more than 10,000 people each year in the UK. One of the biggest challenges in providing treatment is our current lack of knowledge concerning disease development. PD is caused by the death of brain cells in the substantia nigra, but we understand very little of the mechanisms involved. We have recently identified a key role for a protein called HMGB1, which is released when cells die and plays a major role in inflammation. HMGB1 can trigger different cellular pathways all leading to the death of brain cells. We have already demonstrated that inhibition of HMGB1 by a specific antibody and by the liquorice root-derived compound glycyrrhizin, an inhibitor of HMGB1, leads to neuroprotection. Here we propose:
(a) to confirm HMGB1 as the main target for glycyrrhizin,
(b) assess the main structure responsible for HMGB1 inhibition,
(c) generate new compounds based on molecular modelling and
(d) assess these novel compounds in models of PD. Taken together we present a comprehensive study to investigate HMGB1 as a brand new target for a neuroprotective agent, which could revolutionize the treatment of Parkinson’s disease, and potentially other neurodegenerative diseases.
Funding Notes
Funding is available to UK nationals or those EU nationals who can demonstrate that they have been resident in the UK for three years.
Candidates should have (or expect to achieve) a First Class or 2.1 Honours degree in a relevant subject.
When applying, please select Degree of Doctor of Philosophy in Medical Sciences (Science) to ensure that your application is passed to the appropriate College for processing.
Candidates should have (or expect to achieve) a First Class or 2.1 Honours degree in a relevant subject.
When applying, please select Degree of Doctor of Philosophy in Medical Sciences (Science) to ensure that your application is passed to the appropriate College for processing.
References
1. Sathe K*, Maetzler W*, Lang J, Mounsey RB, Fleckenstein C, Martin HL, Schulte C, Mustafa S, Synofzik M, Vukovic Z, Itohara S, Berg D, Teismann P. 2012. S100B is increased in Parkinson’s disease and ablation protects against MPTP-induced toxicity via the RAGE and TNF-α pathway. Brain, 135:3336-47. *equal contribution
2. Teismann P, Sathe K, Bierhaus A, Leng L, Martin HL, Bucala R, Weigle B, Nawroth PP, Schulz JB. 2012. RAGE deficiency protects against MPTP-toxicity. Neurobiol Aging, 33:2478-90.
2. Teismann P, Sathe K, Bierhaus A, Leng L, Martin HL, Bucala R, Weigle B, Nawroth PP, Schulz JB. 2012. RAGE deficiency protects against MPTP-toxicity. Neurobiol Aging, 33:2478-90.
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