Integrin engineering to promote axon regeneration and Schwann cell migration

Lead Research Organisation: University of Cambridge
Department Name: Cambridge Centre for Brain Repair

Abstract

After damage to the spinal cord or brain many nerve fibres are cut. In spinal cord injury this means that motor commands from the brain cannot reach muscles, and sensory information from the skin cannot reach the brain. In order to produce a cure the nerve fibres have to be made to regenerate from the injury point back into the spinal cord and up towards the brain. At present nerve fibre regeneration after spinal cord damage does not succeed, due to many factors such as the scar tissue at the injury site that blocks nerve fibre growth. In the scar tissue there is a molecule called tenascin which nerve fibres could use to grow on, but they lack the receptor molecules to interact with tenascin. The project will put the necessary type of receptor molecules (integrins) on the cut nerve fibres, and will make further modifications to the integrins to prevent them being turned off by inhibitory factors in the scar tissue. A second part of the project is to take a cell type called Schwann cells, which can promote nerve fibre growth, and implant them into spinal cord injuries as a bridge over which the regenerating nerve fibres can grow. In order to make it possible for these cells to integrate into the spinal cord they will also have modifications to their surface integrins.

Technical Summary

The aim of the grant is to develop a new set of tools for structural repair of the damaged spinal cord, base on the manipulation of integrins. By engineering integrin expression, trafficking, activation and signalling we aim to promote axon regeneration, and to increase the ability of Schwann cells to migrate and integrate into the CNS environment. Tenascin-C is upregulated in the damage spinal cord, so we have identified an integran that interacts with it. Proof of principle that expression of a tenascin-binding integrin can promote axon regeneration has already been obtained. However we believe that in the adult CNS inhibitory mechanisms may interfere with integrin activation, trafficking and signalling. We have interventions to counteract these potential influences, and will apply them one by one until we have a successful integrin strategy for promoting CNS repair. This builds on previous work in the applicant?s laboratories on axon regeneration, Schwann cell migration and integrins. It also builds on work by our collaborators on integrin trafficking and activation. The tools for the work are mostly already made, but they have not previously been applied to axon regeneration or Schwann cell migration. The project also builds on spinal cord injury models and methods for behavioural assessment developed in the Fawcett laboratory. Repair of CNS damage will require the integration of several treatments; integrin engineering will probably be an important part of these treatments.

Publications

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Afshari FT (2010) Astrocyte-produced ephrins inhibit schwann cell migration via VAV2 signaling. in The Journal of neuroscience : the official journal of the Society for Neuroscience

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Andrews MR (2009) Alpha9 integrin promotes neurite outgrowth on tenascin-C and enhances sensory axon regeneration. in The Journal of neuroscience : the official journal of the Society for Neuroscience

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Gumy LF (2013) The kinesin-2 family member KIF3C regulates microtubule dynamics and is required for axon growth and regeneration. in The Journal of neuroscience : the official journal of the Society for Neuroscience

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Tan CL (2011) Integrin activation promotes axon growth on inhibitory chondroitin sulfate proteoglycans by enhancing integrin signaling. in The Journal of neuroscience : the official journal of the Society for Neuroscience

 
Description BIRAX
Geographic Reach Europe 
Policy Influence Type Membership of a guideline committee
 
Description Bristol review
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
 
Description advising Novartis and three other pharma companies
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in a advisory committee
 
Description physios
Geographic Reach Europe 
Policy Influence Type Influenced training of practitioners or researchers
Impact changing treatment of spinal injury patients
 
Description MRC
Amount £400,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 06/2008 
End 07/2012
 
Description MS Society Research Grants
Amount £242,367 (GBP)
Organisation Multiple Sclerosis Society 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2018 
End 12/2020
 
Title viral vectors 
Description Viral vectors for expression of integrins, chondroitinase 
Type Of Material Technology assay or reagent 
Year Produced 2009 
Provided To Others? Yes  
Impact Experiments on viral expression of chondroitinase 
 
Description Fassler 
Organisation Max Planck Society
Department Max Planck Institute of Biochemistry
Country Germany 
Sector Public 
PI Contribution We started a collaboration with Reinhard Fassler on integrin activation using kindlins and talin. Fassler provided the tools, the research has been done in Cambridge
Collaborator Contribution tools and knowledge for integrin activators
Impact Paper submitted to J. Neurosci. Kindlin-1 enhances axon growth on inhibitory CSPGs and promotes sensory axon regeneration
Start Year 2009
 
Title alpha9 integrin in axon regeneration 
Description Patent applied for; stimulation of axon regeneration by alpha9 integrin 
IP Reference WO2007083133 
Protection Patent granted
Year Protection Granted 2007
Licensed No
Impact no
 
Description Schools 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Schools
Results and Impact Two talks to local secondary schools.
approx 60 attendees

More applicants to Cambridge
Year(s) Of Engagement Activity 2010,2011
 
Description outreach programme 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Schools
Results and Impact Approx 100 pupils from mostly foreign schools

Interest in university in UK
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010
 
Description physios 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Primary Audience Health professionals
Results and Impact Annual physio meeting

Updates on prospects for spinal injury patients
Year(s) Of Engagement Activity 2009
 
Description spinal injury lawyers 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact updating spinal injury lawyers and patients

changing damages requests
Year(s) Of Engagement Activity 2009
 
Description spinal injury physicians 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Health professionals
Results and Impact Approx 300 spinal injury professionals.
Washington ASIA meeting

Interest in future developments
Year(s) Of Engagement Activity 2011