Promoting Regeneration and Functional Recovery following SCI through Transcriptional Regulation

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Dokumentart: PhDThesis
Date: 2016
Language: English
Faculty: 7 Mathematisch-Naturwissenschaftliche Fakultät
7 Mathematisch-Naturwissenschaftliche Fakultät
Department: Medizin
DDC Classifikation: 000 - Computer science, information and general works
500 - Natural sciences and mathematics
570 - Life sciences; biology
610 - Medicine and health
Keywords: Rückenmarksverletzung , Epigenetik , Regeneration , Rehabilitation , Transkription , Protein p53
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Spinal cord injury (SCI) is a devastating condition due to the permanent neurological deficits it causes, and the abruptness these impairments take place. To date there is no curative therapy for SCI, therefore finding efficient treatment candidates for clinical translation is a compelling need. With the purpose of promoting regeneration and functional recovery after SCI in adult mice, in this work we addressed different but interdependent molecular mechanisms to awake the intrinsic growth machinery of central neurons and to modulate the extrinsic environment within the injury site. It was already known that PCAF also forms a multiprotein complex with CBP/P300 and p53 to drive the transcription of several regeneration associated genes. Thus, our second strategy was to manipulate p53 in order to enhance the p53-dependent regenerative response and improve functional recovery. By disrupting the p53 interaction with its main negative regulators MDM2 or MDM4, either by local Nutlin-3a inhibition or conditional deletion in SMC neurons, respectively, we enhanced p53 transactivation. This led in fact to increased sprouting of descending tracts and improved locomotor behavior of adult mice after SCI without increasing cell death. Furthermore, we showed for the first time that these pro-regenerative effects of p53 are dependent on IGF1 signaling. Nutlin-3a is already under scrutiny in clinical trials for cancer therapy and might be clinically available in the near future. Therefore this work opens an exciting possibility to bring a new candidate for translation in the SCI clinical context.

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