Development is a vectorial process that is necessarily under the control of multiple genes and their regulatory interactions. The handful of developmental genetic regulatory networks that have been deciphered to date reveal embryonic development to involve large, multi-layered networks, nonlinear regulatory processes, and complex dynamics mediated by multiple feedforward, lateral, and feedback interactions. Because of these characteristics, development can only be properly understood within the framework of systems biology. A particularly important model to understand is blood cell development. All blood cells are generated continuously throughout life from hematopoietic stem cells (HSC), via tightly regulated developmental processes that are disrupted in a number of major blood diseases. Developing precursors of each of the diverse blood cell types are defined not only by their acquisition of mature characteristics but also by the degree of access they retain to alternative blood-cell differentiation pathways. T lymphocyte differentiation from HSC is a system that offers unusually clear access to the time course of a developmental choice and the intermediate stages through which it passes. T-lineage fate selection is based on a protracted competition among regulatory inputs, which precursor cells only resolve after many cell cycles. This project will use computational and experimental studies of T-cell development to decipher how environmental and intrinsic regulatory inputs are integrated to drive mammalian blood stem cells to choose among different leukocyte developmental fates, and to make the transition from plasticity to commitment. Hamid Bolouri will lead the computational component of the project. His group will develop computational methods for prediction and integration of protein-protein and protein-DNA interactions with gene perturbation data to generate a series of alternative gene-network hypotheses. His group will use formal statistical model selection to refine kinetic models of network operation. These computational predictions will guide the experimental program and interpret the data it generates. Ellen Rothenberg will lead the experimental component of the project. The Rothenberg group will use in vitro differentiation systems, gene-specific perturbations, and quantitative multigene expression data to dissect regulatory network relationships that guide T-cell emergence from stem cells. The kinetics of this process will also be tracked for individual cells. Specific hypotheses tested in the perturbations will be refined iteratively through ongoing interaction with the modeling studies done by the Bolouri group. Blood cells are generated from stem cells throughout life, and many human diseases trace their origin to a derangement in the complex regulation of blood-cell developmental processes. T-cell development has many features that make it an excellent system in which to study the mechanisms that control cell fate choice and the rigorous regulatory mechanisms that guide immature cells away from abnormal fates. Through a dialogue between computational modeling and experimental analysis, we will explain the regulatory network that makes T-cell development robust, providing new insights into mechanisms that can prevent disease.
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