Molekulare Strategien zur Unterstützung der funktionalen Reinnervation des mit Zellimplantation behandelten Harnröhrensphinkters unter Verwendung eines neuen auf p-53 basierenden Ansatzes.

• Applicant: Professor Dr. Simone Di Giovanni
• Subject Area: Reproductive Medicine, Urology
• Term: from 2012 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 190473765

• Final Report Year: 2016

Final Report Abstract

In summary we found that p53-MDM2/4-IGF1 signaling is essential for axonal regeneration of corticospinal and raphespinal axons after a SCI. Axonal regeneration requires p53 and IGF1. In fact IGF1 is required for p53 dependent enhancement of axonal sprouting and regeneration of 5-HT raphespinal and CST axons after SCI. Furthermore, Nutlin-3 delivery that enhances p53-IGF1 pathway, promotes recovery of sensorimotor and urinary impairments. Ultimately, these studies provided a novel understanding of p53-dependent pathways and of the role of p53-IGF1 in the control of axonal sprouting and regeneration as well as functional recovery after SCI.

Publications

• P53 regulates the neuronal intrinsic and extrinsic responses affecting the recovery of motor function following spinal cord injury. J Neurosci. 2012 Oct 3;32(40):13956-70
  Floriddia EM, Rathore KI, Tedeschi A, Quadrato G, Wuttke A, Lueckmann M, Kigerl KA, Popovich PG, Di Giovanni S
  (See online at https://doi.org/10.1523/JNEUROSCI.1925-12.2012)
• The transcription factor serum response factor (SRF) stimulates axon regeneration through cytoplasmic localization and cofilin interaction. J Neurosci. 2013. Nov 27;33(48):18836-48
  Stern S, Haverkamp S, Sinske D, Tedeschi T, Naumann U, Di Giovanni S, Kochanek S, Nordheim A, and Knöll, B
  (See online at https://doi.org/10.1523/JNEUROSCI.3029-13.2013)
• The tumor suppressor p53 fine-tunes ROS levels and neurogenesis via PI3K signaling. J Neurosci. 2013 Sep 4;33(36):14318-30
  Forsberg K, Wuttke A, Quadrato G, Chumakov PM, Wizenmann A, and Di Giovanni S
  (See online at https://doi.org/10.1523/JNEUROSCI.1056-13.2013)
• DNA methylation temporal profiling following peripheral versus central nervous system axotomy. Scientific Data 11 Sept 2014
  Lindner R, Puttagunta R, Nguyen T, Di Giovanni S
  (See online at https://doi.org/10.1038/sdata.2014.38)
• PCAF-dependent epigenetic changes promote axonal regeneration in the central nervous system. Nature Comm. 2014 Apr 1;5:3527
  Puttagunta R, Tedeschi A, Soria MG, Lindner R, Rahthore KI, Gaub P, Joshi Y, Nguyen T, Schmandke A, Bradke F, Di Giovanni S
  (See online at https://doi.org/10.1038/ncomms4527)
• The MDM4/MDM2-p53-IGF1 axis controls axonal regeneration, sprouting and functional recovery after CNS injury. Brain. 2015 Jul;138(Pt 7):1843-62
  Joshi Y, Soria M, Quadrato G, Inak G, Zhou Z, Hervera A, Rathore K, Elnagger M, Magali C, Marine JC, Puttagunta R, Di Giovanni S
  (See online at https://doi.org/10.1093/brain/awv125)