Ruprecht-Karls-Universit├Ąt Heidelberg
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Grimm_Villalba0118 - Scientist (f/m) / PhD position
Project no:

Project leader:

Project supervisor:
Grimm, Dirk
Martin-Villalba, Ana
Application deadline:
31. Mar 2018
Start of PhD project:
1. Apr 2018

Project description:

Back to the future - breaking the barriers of cellular reprogramming and tissue regeneration in vivo
The ability to reprogram cells into induced pluripotent stem cells (iPSC) by over-expressing a set of four transcription factors ("OKSM") has revolutionized regenerative medicine, but clinical translation is hampered by the difficulty to apply the approach directly in vivo. Likewise, the discovery of stem cells in adult tissues has spurred hopes that these could replace dying cells following injury, but their efficiency and versatility are often too low for therapeutic benefit.
Here, we will break new scientific ground, by attempting to partially reprogram adult stem cells within a tissue in a living organism to enable tissue repair in situ. To this end, we will engineer Adeno-associated viral (AAV) gene delivery vectors for targeted OKSM transfer to neural stem cells (NSC) in the mouse brain, following injection into the lateral ventricles. To elude adverse formation of teratomas (benign tumors) due to unrestricted OKSM expression, we will implement two strategies that permit exogenous control over AAV vector expression. The new vectors will then be tested in a clinically relevant mouse model of brain damage after cardiac arrest, i.e., transient global cerebral ischemia induced by bilateral common carotid artery occlusion.
Our key hypothesis is that spatio-temporally controlled OKSM expression will enhance the capacity of NSC to replace at least three different cellular subtypes that are needed for functional recovery of the damaged brain. If successful, our interdisciplinary and pioneering work merges, for the first time, two of the most powerful biomedical techniques in vivo and will thereby lay the foundation for entirely novel clinical modalities.
Gonzalez, F., Boue, S. & Izpisua Belmonte, J.C. Methods for making induced pluripotent stem cells: reprogramming a la carte. Nat Rev Genet 12, 231-242 (2011)

Grimm, D. & Zolotukhin, S. E Pluribus Unum: 50 Years of Research, Millions of Viruses, and One Goal-Tailored Acceleration of AAV Evolution. Mol Ther 23, 1819-1831 (2015)

Ocampo, A. et al. In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming. Cell 167, 1719-1733 e1712 (2016)

Seo, J.H. et al. In Situ Pluripotency Factor Expression Promotes Functional Recovery From Cerebral Ischemia. Mol Ther 24, 1538-1549 (2016)

Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663-676 (2006)
Methods that will be used:
A wide variety of state-of-the-art molecular, genetic, biochemical, virological and cell biological technologies, including stem cell methodologies, viral vector design and production, and work in a physiologically relevant mouse model of human brain damage.
Cooperation partners:
Dr. Dominik Niopek (German Cancer Research Center Heidelberg)
Personal qualifications:
- diploma or MSc in biology, molecular medicine or any related discipline
- genuine interest in translational research, especially in regenerative medicine and/or gene therapy
- high motivation for team work and for collaborative projects
- prior experience in stem cell research, virology, vectorology, mammalian cell culture and/or animal work are beneficial, but not required
regenerative medicine, cellular reprogramming, iPSC, gene therapy, viral vectors