Impact of peripheral inflammation on cerebrovascular disease

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

Abstract

The blood supply to the brain provides essential oxygen and nutrients to support brain function. During stroke the blood supply to the brain may be reduced or blocked. This causes nerve cells in the brain to die, which can be fatal for the patient or leave them severely disabled. Although some treatments are available for stroke, these are not suitable for all patients and not always widely effective. We need therefore to understand more about why stroke occurs and what causes the brain cells to die so that new treatments can be developed.

Inflammation is the response of the body to fight infection, but it can also lead to a variety of diseases, such as arthritis and asthma. The inflammation that occurs outside the brain, for example in a blood vessel, can contribute to the development of conditions such as stroke and make the patient much worse. Therefore in this proposal our aim is to understand how inflammation and infection outside the brain affect events within the brain. To do this we will study animals that develop disease of their blood vessels in much the same way that many humans do, to see if this causes strokes and, if so, how. The studies should help us to identify better animal models of human stroke in which to test new treatments. We also aim to discover substances within the blood or brain that can predict the occurrence of brain diseases such as stroke, so that patients can be treated early.

Technical Summary

The problem:
Inflammation is increasingly recognised as a key contributor to diverse diseases including cancer, diabetes, atherosclerosis and CNS disorders, such as Alzheimer?s and Parkinson?s disease. A growing literature also suggests that peripheral inflammation can induce cardiovascular and cerebrovascular disease, and profoundly influences outcome. Our recent studies have begun to elucidate how experimental cerebral ischaemia (CI) causes peripheral inflammatory changes, and how systemic inflammation influences outcome from CI.
Overall aim and hypotheses:
The overall aim of this project is to identify the mechanisms and mediators through which different forms of peripheral inflammation influence CI, and to identify potential treatments and biomarkers of disease incidence and severity of outcome. Our hypothesis is that, while CI is a disorder of neurological consequences, its origin is largely systemic and as such it should be treated as a vascular disorder, comparable to coronary or other vascular diseases.
Specific objectives are to:
1. Determine the mechanisms by which (a) experimental CI induces a peripheral inflammatory response, and (b) how this acute peripheral inflammation then influences the response to CI.
2. Test the hypothesis that chronic vascular inflammation causes cerebrovascular pathology and/or CI in (a) the absence or (b) the presence of an acute peripheral inflammatory event.
3. Determine (a) the impact of chronic vascular inflammation on responses to CI, and (b) the mechanisms underlying effects of inflammation on cerebrovascular pathology.
4. Identify new biomarkers for the risk of CI and the severity of outcome.
Expected outcomes:
We expect that this programme would:
i. Identify mechanisms through which peripheral inflammation influences cerebrovascular (and potentially other vascular) disease and hence identify targets for therapeutic intervention.
ii. Establish more clinically relevant animal models of disease.
iii. Identify biomarkers of disease and potential outcome in animals that we could subsequently test in patients.
These studies are designed to parallel our ongoing clinical research on the systemic drivers of CI, their role in clinical outcome and validation of potential treatments.

Publications

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Murray KN (2013) Systemic immune activation shapes stroke outcome. in Molecular and cellular neurosciences

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Pradillo JM (2012) Delayed administration of interleukin-1 receptor antagonist reduces ischemic brain damage and inflammation in comorbid rats. in Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism

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Smith CJ (2013) The immune system in stroke: clinical challenges and their translation to experimental research. in Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology

 
Description Research Grant
Amount £275,000 (GBP)
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 05/2013 
End 04/2016
 
Description Testing of Novartis's anti-IL-1beta antibody in cerebral ischaemia and neuroinflammation 
Organisation Novartis
Country Global 
Sector Private 
PI Contribution We will test this antibody for neuroprotection in experimental models of cerebral ischaemia and neuroinflammation.
Collaborator Contribution Provision of material for studies
Impact Cerebral ischaemia experiments ongoing. Neuroinflammation experiments finished (in collaboration with cardiovascular colleagues at the University of Sheffield - 3-way agreement); paper in preparation and pending approval from Novartis prior to submission.
Start Year 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 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 Keynote talk at Stroke Assembly 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact An annual event that enables stroke survivors and their families to express their opinions and hopes in a UK-wide forum. This was held in 2013 at Nottingham University. Around 200 people attended and participated in discussions around our research.

Not yet known
Year(s) Of Engagement Activity 2013
URL http://www.strokeassembly.org.uk/content/brains-fire
 
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 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
 
Description World Stroke Day 2012 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Type Of Presentation Poster Presentation
Geographic Reach Regional
Primary Audience Participants in your research and patient groups
Results and Impact 160 people (patients, carers, health care professionals) attended a World Stroke Day event organised by the Northwest Local Stroke Research Network at Wigan Stadium. We ran a series of table-top activities alongside posters to engage the attendees with our research. Grant holders, postdocs and students were all involved.

Not known at this time
Year(s) Of Engagement Activity 2012