The transitions from egg to embryo to adult require that cells communicate with each other to acquire specialized fates at the right times in the correct places. Cancer is in part the result of aberrant regulation. Most of our information on signaling pathways comes from genetics and biochemistry on populations of cells, with stimuli typically reduced to a binary on/off. This project will adapt contemporary microfluidic technology to accurately control the concentrations of signaling molecules in time in multiple small chambers while continuously imaging the response of single cells via fluorescently tagged proteins that move in response to signals. We will use human embryonic stem cells (hESC) for this purpose because of their relevance to regenerative medicine. We will stimulate the cells with ligands from the TGF? pathway since they can induce the first round of developmental choices these cells naturally make. This pathway has two sub-branches that interfere, making it a natural context in which to study pathway interactions. Our data will be organized and developed into a predictive tool with which to rationally reprogram specialized fates from hESCs.

Public Health Relevance

To use human embryonic stem cells for regenerative medicine requires the ability to direct the differentiation of these cells to the required fates without causing genetic damage. We will follow the first steps of stem cell differentiation using new high-resolution techniques drawn from Physics and integrate the results using topological methods into predictive models.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM101653-02
Application #
8513376
Study Section
Special Emphasis Panel (ZRG1-BST-M (50))
Program Officer
Gaillard, Shawn R
Project Start
2012-07-19
Project End
2016-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
2
Fiscal Year
2013
Total Cost
$314,868
Indirect Cost
$129,105
Name
Rockefeller University
Department
Physics
Type
Other Domestic Higher Education
DUNS #
071037113
City
New York
State
NY
Country
United States
Zip Code
10065
Yoney, Anna; Etoc, Fred; Ruzo, Albert et al. (2018) WNT signaling memory is required for ACTIVIN to function as a morphogen in human gastruloids. Elife 7:
Martyn, I; Kanno, T Y; Ruzo, A et al. (2018) Self-organization of a human organizer by combined Wnt and Nodal signalling. Nature 558:132-135
Deglincerti, Alessia; Etoc, Fred; Guerra, M Cecilia et al. (2016) Self-organization of human embryonic stem cells on micropatterns. Nat Protoc 11:2223-2232
Deglincerti, Alessia; Etoc, Fred; Ozair, M Zeeshan et al. (2016) Self-Organization of Spatial Patterning in Human Embryonic Stem Cells. Curr Top Dev Biol 116:99-113
Deglincerti, Alessia; Haremaki, Tomomi; Warmflash, Aryeh et al. (2015) Coco is a dual activity modulator of TGF? signaling. Development 142:2678-85
Warmflash, Aryeh; Sorre, Benoit; Etoc, Fred et al. (2014) A method to recapitulate early embryonic spatial patterning in human embryonic stem cells. Nat Methods 11:847-54
Sorre, Benoit; Warmflash, Aryeh; Brivanlou, Ali H et al. (2014) Encoding of temporal signals by the TGF-? pathway and implications for embryonic patterning. Dev Cell 30:334-42
Siggia, Eric D; Vergassola, Massimo (2013) Decisions on the fly in cellular sensory systems. Proc Natl Acad Sci U S A 110:E3704-12
Ozair, Mohammad Zeeshan; Noggle, Scott; Warmflash, Aryeh et al. (2013) SMAD7 directly converts human embryonic stem cells to telencephalic fate by a default mechanism. Stem Cells 31:35-47
Warmflash, Aryeh; Arduini, Brigitte L; Brivanlou, Ali H (2012) The molecular circuitry underlying pluripotency in embryonic stem cells. Wiley Interdiscip Rev Syst Biol Med 4:443-56

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