Grant: Operating Grant

Pluripotency, the ability to develop into any cell type in our bodies, is a powerful fundamental system to study cellular decision-making processes during human development and disease. Unfortunately, our incomplete understanding of the molecular and cellular networks that regulate the gain or loss of this cell state limits translational applications of pluripotent stem cells (PSCs). For example, how can we imagine using PSCs to robustly generate functional tissue for cell therapy or drug screening if we don't really understand how the gene and cell networks that are reasonable for harnessing this development potential are coded, and ultimately modified, to generate specific cell types? Our central goals are to understand in a predictive and quantitative manner how pluripotent networks are stabilized, and to identify the regulatory gene and cellular network control points (i.e. triggers) that lead to PSC commitment into early tissue types. Our group is ideally suited to achieve these important goals as we have relatively unique and deep expereince in the development and implementation of mathematical models and technologies to stimulate and control PSC organization and signalling, enabling rapid and predictive in silico (or "in computer") experiments of development and disease. This project will specifically asks the following questions" how do different pluripotent cell states exist, each with their own unique intracellular signalling and gene regulatory networks; how does the local microevironment input signals into these networks to control or modify PSC fate; and how are these two levels of cell fate control (inside individual call and between different cells) integrated to generate stem cells that can form functional tissues? In addition to yielding fundamental new knowledge on call fate control during early tissue development, this project will yield translational technologies applicable to drug screening and cellular therapeutic strategies.