IL-1 and neurodegeneration

Lead Research Organisation: University of Manchester
Department Name: Life Sciences

Abstract

Nancy Rothwell has given numerous lectures (including many live demonstrations) to the public and schools, on many topics in research. She is currently President of the Medical Section of the BA and an active member of the European DANA Alliance for the Brain. She has written many articles for non-scientists about her own research, research careers and particularly on the importance of animals in medical research.

Stuart Allan has given several public lectures and has been directly involved in the supervision of school children during visits to our lab. We often host school children on work experience in our lab.

The School of Biological Sciences now holds a formal course for graduates and post docs in public engagement in science. Many members of our lab participate in these activities through visits to schools, talks and supervising visitors. We consider that these activities are extremely important and they are actively encouraged.

Technical Summary

Our ultimate goal is to understand the mechanisms underlying neuronal death, and thus to develop novel therapeutic approaches for neurodegenerative disorders, by identifying the mechanisms of action of the cytokine interleukin-1 (IL-1).

We demonstrated that IL-1 mediates experimentally induced ischaemic, excitotoxic and traumatic brain injury. We showed that the naturally occurring IL-1 receptor antagonist (IL-1ra) is a potent neuroprotective agent, which is now in early clinical trials in stroke.
The aim of this programme is to determine how IL-1 mediates and exacerbates neuronal injury.
To do this we will address three fundamental questions, based on our recent observations:

1) How does IL-1 mediate neuronal death?
We will test the hypotheses that IL-1:
i) acts on non-neuronal cells to release (as yet unidentified) neurotoxins.
ii) primes neurones for cell death.
iii) mediates or exacerbates neuronal death in vivo through actions on local blood flow, local brain temperature and/or increased seizure activity.
In each case we will subsequently investigate the mediators and mechanisms.

2) Which receptors mediate IL-1 actions in the brain?
We will further test our hypothesis that IL-1 acts through new receptors, and identify IL-1 signalling mechanisms.

3) What is the role of newly identified members of the IL-1 family?
We will test the hypothesis that new IL-1 ligands contribute to neurodegeneration and/or interact with the known IL-1 system.
This programme combines molecular, cellular and whole animal approaches. We have extensive preliminary data, experience, and unique access to reagents. The results could lead to new treatments for neurodegenerative disorders.

Publications

10 25 50

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Prenant C (2010) Radiolabeling with fluorine-18 of a protein, interleukin-1 receptor antagonist. in Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine

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McColl BW (2010) Increased brain microvascular MMP-9 and incidence of haemorrhagic transformation in obese mice after experimental stroke. in Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism

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Luheshi NM (2009) The dynamics and mechanisms of interleukin-1alpha and beta nuclear import. in Traffic (Copenhagen, Denmark)

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Summers L (2009) Adhesion to fibronectin regulates interleukin-1 beta expression in microglial cells. in Molecular and cellular neurosciences

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Chapman KZ (2009) A rapid and transient peripheral inflammatory response precedes brain inflammation after experimental stroke. in Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism

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Skinner RA (2009) Transport of interleukin-1 across cerebromicrovascular endothelial cells. in British journal of pharmacology

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McColl BW (2008) Systemic inflammation alters the kinetics of cerebrovascular tight junction disruption after experimental stroke in mice. in The Journal of neuroscience : the official journal of the Society for Neuroscience

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Denes A (2007) Proliferating resident microglia after focal cerebral ischaemia in mice. in Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism

 
Description BBSRC Project Grant (Combinatorial Systems Biology of ROS-Regulated Interleukin-1 Gene Expression)
Amount £608,148 (GBP)
Funding ID BB/F018398/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 10/2008 
End 09/2011
 
Description Developmental Clinical Studies
Amount £600,000 (GBP)
Funding ID G1001252 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 05/2011 
End 04/2014
 
Description EU FP7 grant
Amount € 857,000 (EUR)
Organisation European Commission 
Department Seventh Framework Programme (FP7)
Sector Public
Country European Union (EU)
Start 03/2008 
End 02/2013
 
Description MRC Experimental Medicine Grant
Amount £520,000 (GBP)
Funding ID G0502030 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 12/2006 
End 12/2010
 
Description MRC Models of Disease Grant
Amount £640,000 (GBP)
Funding ID G0801040 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 12/2008 
End 08/2012
 
Description MRC Research Grant (NMHB)
Amount £800,000 (GBP)
Funding ID G0801296 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 02/2009 
End 01/2012
 
Description MRC Research Grant (PSMB)
Amount £800,000 (GBP)
Funding ID G0802001 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 10/2009 
End 09/2013
 
Description Wellcome Trust Career Development Fellowship
Amount £720,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start  
 
Description Microarray analysis and support of PhD student 
Organisation Syngenta International AG
Country Switzerland 
Sector Private 
PI Contribution The PhD student funded by this CASE-studentship was fully trained and conducted all microarray analyses under the supervision of the industrial partner (Prof Ian Kimber). Specific genes of interest found on the microarray chip, were further test by our research team.
Collaborator Contribution microarray analysis and support of PhD student
Impact One collaborative paper published: Tsakiri N., Kimber I., Rothwell N.J., Pinteaux E. (2008) Differential effects of IL-1a and IL-1b on IL-6 and chemokines synthesis in neurones. Mol. Cell. Neurosci. 38, 259-265. PubMed ID 18722361.
 
Description Provision of Amgen IL-1RA for clinical studies 
Organisation Amgen Inc
Country United States 
Sector Private 
PI Contribution Carried out pharmacokinetic study to identify optimal dosing regime of IL-1RA in SAH patients.
Collaborator Contribution Provision of IL-1RA for clinical studies
Impact Pharmacokinetic study identified optimal dosing regime of IL-1RA in SAH patients to take forward to test efficacy in further trials. Phase II randomised controlled double blind trial (IL-1RA vs placebo) now completed in SAH patients (analysis in progress).
 
Description Studies of Allostera's IL-1R antagonist in neuroprotection against cerebral ischaemia 
Organisation Allostera Pharma
Country Canada 
Sector Private 
PI Contribution Performed initial studies with material to test for neuroprotection in experimental models of cerebral ischaemia.
Collaborator Contribution Provision of material for studies
Impact Results from initial studies were promising, therefore currently arranging research contract for futher studies. Nov. 2010 update: company closed down, therefore contract terminated.
Start Year 2008
 
Description Studies of Amgen's interleukin-1 receptor antagonist (IL-1RA) in neuroprotection against cerebral ischaemia 
Organisation Amgen Inc
Country United States 
Sector Private 
PI Contribution Carried out in vitro and in vivo preclinical studies of IL-1RA in cerebral ischaemia, leading to phase II trials in stroke and subarachnoid haemorrhage (SAH) patients (Experimental Medicine grant G0502030).
Collaborator Contribution Provision of material for studies
Impact Results of preclinical studies have lead to phase II trial in stroke patients (Sir Jules Thorn Charitable Trust grant - pre-2006), pharmacokinetic study in subarachnoid haemorrhage (SAH) patients (Experimental Medicine grant G0502030 - just completed)) and phase II randomised controlled double blind trial (IL-1RA vs placebo) in SAH patients (Experimental Medicine grant G0502030 - ongoing). Amgen has since sold the licence for IL1-RA to Swedish Orphan Biovitrum, so currently setting up a 3-way agreement with both companies for IL-1RA for further preclinical studies. Nov. '11: 3-way agreement finalised, material received, and preclinical neuroprotection experiments ongoing.
 
Description UCB CASE studentship 
Organisation UCB Pharma
Country United Kingdom 
Sector Private 
PI Contribution Funded PhD student to investigate inflammatory responses to experimental stroke
Collaborator Contribution Provided equipment and support for multiplex analysis of samples.
Impact Paper published (PubMed ID 19654587) and oral presentation at international conference
Start Year 2006
 
Title New use for IL-1RA to treat neurodegeneration 
Description Collaboration with Amgen Inc. to test the clinical utility of IL-1RA for stroke in man. The first clinical phase II study was completed in 2004. Patent granted initially in US in 2000; other international applications went to grant in 2002, 2003, 2004 and 2008. 
IP Reference WO1993008820 
Protection Patent granted
Year Protection Granted
Licensed No
Impact The data gathered suggest that rhIL-1RA is safe and well tolerated in acute stroke. In addition, rhIL-1RA exhibited biological activity that is relevant to the pathophysiology and clinical outcome of ischaemic stroke. These data demonstrate that rhIL- 1RA has potential as a new therapeutic agent for acute stroke. A pharmacokinetic study of IL-1RA in SAH patients has just been completed(Experimental Medicine grant G0502030).
 
Description All types and numerous locations; numerous examples 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Primary Audience Schools
Results and Impact Numerous scientific, public and policy talks - too many to detail.

Significant press coverage
Year(s) Of Engagement Activity 2006,2007,2008,2009
 
Description Annual STARS lecture, Manchester 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Schools
Results and Impact Annual STARS lecture to ~200 local sixth form and college students.
Title: 'A stroke of bad luck: Understanding brain disease' (targeted at A level Biology).

Not known.
Year(s) Of Engagement Activity 2011
 
Description Event for stroke patients and carers, Nov. 2010 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Participants in your research and patient groups
Results and Impact 10 stroke survivors/carers attended an event called "Stroke research - from test tube to treatment", which comprised talks from 3 researchers, spanning preclinical to clinical studies, and interacted with post-docs and students over various displays and refreshments. The feedback from attendees was mostly very positive and all but one expressed an interest in attending future events. The constructive feedback has made us re-evaluate what we want to achieve from such events and will inform future events.

We are re-evaluating the aims of such events and are planning further, larger events, taking into account the feedback received from this meeting. Specifically, we will be involved in a large event for World Stroke Day 2011, with our clinical colleagues.
Year(s) Of Engagement Activity 2010
 
Description Frontiers of Science talk, Uni of Manchester 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact Frontiers of Science talk delivered to ~150 undergraduate students from 1st year to 3rd year, followed by questions and discussion.
Title: "Flaming brains - new discoveries about brain disease"


No specific impact known.
Year(s) Of Engagement Activity 2011
 
Description Give approx. 10-12 public and schools lectures each year (too numerous to detail) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Schools
Results and Impact Give approx. 10-12 public and schools lectures each year (too numerous to detail)

Not possible to detail specific impacts - aim to increase interest in science, particularly in underprivileged areas. Often receive requests from school students wishing to do work experience in the lab, following a talk at their school (all of whom we aim to accommodate wherever possible).
Year(s) Of Engagement Activity 2009
 
Description Keynote lecture to Schools Science Conference 2011 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Primary Audience Schools
Results and Impact Talk followed by Q&A session. Title: "A stroke of bad luck - new discoveries in the treatment of brain disease". Session: Science is the Future.
Venue : Royal College of Pathologists, London
Audience : 50 secondary year students from years 10-13 and their teachers

No specific impact known.
Year(s) Of Engagement Activity 2011
 
Description Lecture at the University of Birmingham 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact Talk title: "A stroke of bad luck: mechanisms and treatments for brain disease". For ~200 Uni staff and students. Followed by questions and discussion.

No specific impact known.
Year(s) Of Engagement Activity 2011
 
Description Numerous scientific, public and policy talks - too many to detail 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact Numerous scientific, public and policy talks - too many to detail.

Significant press coverage
Year(s) Of Engagement Activity 2006,2007,2008
 
Description World Stroke Day 2011 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Primary Audience Participants in your research and patient groups
Results and Impact World Stroke Day event in Oct. 2011 organised by our clinical colleagues. The clinical investigator Dr Tyrrell presented the results of the clinical study funded by this grant. The audience comprised ~180 stroke patients and their carers, healthcare professionals and associated charities/organisations.

Not known.
Year(s) Of Engagement Activity 2011