Mechanisms of Schwann cell myelination and dedifferentiation: relevance to nerve repair and pathology. (360G-Wellcome-091119_Z_10_Z)
In view of the importance of Schwann cell dedifferentiation for nerve pathology/repair, it is surprising how little is known about the relevant transcriptional programmes. Our identification of two transcriptional regulators in Schwann cells, Notch and c-Jun, that control this process is therefore a significant step forward. (A) We will test (i) whether c-Jun-dependent Schwann cell signals control neuronal survival/growth after injury and whether such signals promote neuropathic pain (ii) h ow Schwann cell c-Jun controls breakdown of axon-growth inhibitors and organises cell morphology to generate growth-substrate for axons (iii) the direct transcriptional regulation by c-Jun in Schwann cells of genes important for nerve repair. (B) We will analyse how (i) c-Jun and Notch pathways cross-talk in Schwann cells of injured nerves and (ii) Notch inhibits repair while c-Jun promotes it. (C) Lastly we will test whether, in principle, c-Jun and Notch signalling can be targeted to i mprove pathology in animal models of inherited and acquired demyelinating disease, and nerve regeneration following injury. We will use genetically modified mice, including mice with conditional inactivation of c-Jun, conditional activation of c-Jun, conditional inactivation of Notch, inactivation of the c-Jun/Notch ubiquitin ligase Fbw7 and the transcription factor Olig1, and genetic models of demyelinating disease.
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Grant Details
Amount Awarded | 1284915 |
Applicant Surname | Jessen |
Approval Committee | Neurosciences And Mental Health |
Award Date | 2010-02-18T00:00:00+00:00 |
Financial Year | 2009/10 |
Grant Programme: Title | Programme Grant |
Internal ID | 091119/Z/10/Z |
Lead Applicant | Prof Kristjan Jessen |
Other Applicant(s) | Prof Rhona Mirsky |
Partnership Value | 1284915 |
Planned Dates: End Date | 2017-05-31T00:00:00+00:00 |
Planned Dates: Start Date | 2010-06-01T00:00:00+00:00 |
Recipient Org: Country | United Kingdom |
Region | Greater London |