The classical view of cellular decision making is that individual cells make predictable choices based on the information presented to them in the form of both environmental and intracellular signals. However, recent theoretical and experimental studies have unambiguously shown that biological noise, typically arising from inherent stochasticity in underlying biochemical reactions or variability in cellular machinery, ca often play a crucial role in influencing cell fate outcomes. In this proposal, we examine the interconnected roles of signaling and noise in cell differentiation and we hypothesize that noise in cell signaling molecules can engender entirely new trajectories from one cell state to another. We will use computational and synthetic biology approaches to understand how such trajectories may arise, and we will use systems biology approaches to experimentally demonstrate and manipulate these trajectories in model systems of neurogenesis and hematopoiesis. The results of our study will yield deeper insights into the fundamental mechanisms underlying cellular decision making, particularly in differentiation, and should allow for more robust engineering of stem and progenitor cells for applications in regenerative medicine.
A better understanding of the interplay between cell signaling and noise has broad relevance to public health, since the insights gained from our study should aid in the robust engineering of new tissues from stem and progenitor cells. This work will also improve our understanding of life-threatening ailments such as cancer and infectious diseases, since cell heterogeneity is a vital factor in their progression.
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|Shah, Najaf A; Levesque, Marshall J; Raj, Arjun et al. (2015) Robust hematopoietic progenitor cell commitment in the presence of a conflicting cue. J Cell Sci 128:3009-17|