Human induced pluripotent cells (hiPSC) hole enormous promise for regenerative medicine. We propose to explore new methodologies to generate hiPSC without the use of transgene vectors and to develop ways to understand the kinetics, biochemistry and molecular biology of the reprogramming process. In the first part, we have built systems where individual or combinations of reprogramming factors can be controlled artificially and robustly. This will allow us to address questions regarding the temporal sequence of factor requirement, the duration of factor expression necessary for successful reprogramming and other issues. This system will also set the stage for both broad and focused chemical genomics approaches to identify chemical compound that replace individual or combinations of reprogramming factors. The second part builds of results from the first and will explore the dynamics of reprogramming at the epigenetic, transcriptional, steady state mRNA and proteomic levels. This will provide key mechanistic insights into how reprogramming occurs and into the very nature of the pluripotent state.

Public Health Relevance

The proposed studies will provide a better understanding of the reprogramming process by which adult human cells can be converted to induced pluripotent cells (hiPSC). These cells can be derived from patients and will provide important insights into the etiology of complex diseases and potential cell replacement therapies in the future. Other proposed studies will provide more efficient and safer, clinically applicable approaches to generate hiPSC.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
NIH Challenge Grants and Partnerships Program (RC1)
Project #
1RC1GM091176-01
Application #
7821574
Study Section
Special Emphasis Panel (ZRG1-BDA-A (52))
Program Officer
Haynes, Susan R
Project Start
2010-04-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2012-03-31
Support Year
1
Fiscal Year
2010
Total Cost
$999,999
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Xu, Huilei; Baroukh, Caroline; Dannenfelser, Ruth et al. (2013) ESCAPE: database for integrating high-content published data collected from human and mouse embryonic stem cells. Database (Oxford) 2013:bat045
Xu, Huilei; Lemischka, Ihor R; Ma'ayan, Avi (2010) SVM classifier to predict genes important for self-renewal and pluripotency of mouse embryonic stem cells. BMC Syst Biol 4:173
Xu, Huilei; Schaniel, Christoph; Lemischka, Ihor R et al. (2010) Toward a complete in silico, multi-layered embryonic stem cell regulatory network. Wiley Interdiscip Rev Syst Biol Med 2:708-33
Macarthur, Ben D; Ma'ayan, Avi; Lemischka, Ihor R (2009) Systems biology of stem cell fate and cellular reprogramming. Nat Rev Mol Cell Biol 10:672-81