Edenhofer

Project Title: Exploring novel molecular tools and strategies to analyze pluripotency induction in somatic cells and to derive factor-free iPS cells

The discovery that adult somatic cells can be reprogrammed into induced pluripotent (iPS) cells by a combination of factors holds immense promise for a wide range of biological and therapeutic applications. iPS cells could provide a virtually unlimited source for modeling human diseases and screening potential drugs in the cell culture dish. However, crucial safety issues have to be addressed in order to make iPS cells clinically useful. The viral transduction method conventionally used for iPS derivation carries the risk of oncogenic transformation. Additionally, some of the reprogramming genes play a role in tumor formation. A thorough understanding of the mechanism underlying reprogramming would pave the way to establish robust and effective protocols to derive safe iPS cells. However, although iPS research has progressed rapidly within the past years the reprogramming mechanism remained largely obscure. Our proposal aims at implementing and developing novel molecular strategies and tools to gain mechanistic insight into the process of reprogramming and using this knowledge to enhance iPS derivation. In particular, we will use cell-permeant biologically active reprogramming factors - developed in our laboratory during the first period of funding - to produce iPS cells from human somatic cells in a robust and standardized manner. In combination with loss-of-function paradigms conditionally induced by site-specific recombinases and gain-of-function by hormones we intend to reach a so far unattained level over the activity of reprogramming factors that will be instrumental to characterize the establishment of pluripotency at a molecular level.