Reverse engineering genetic network architecture for stem-cell/lymphocyte transit

用于干细胞/淋巴细胞转运的逆向工程遗传网络架构

• 批准号: 7487780
• 负责人: Hamid Bolouri
• 金额: $ 30.8万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-22 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7487780
• 关键词: Blood; Blood Cells; Cell Cycle; Cell Differentiation process; Cell Fate Control; Cells; Characteristics; Complex; Computer Architectures; Computer Simulation; Computing Methodologies; DNA-Protein Interaction; Data; Development; Developmental Process; Disease; Embryonic Development; Experimental Models; Feedback; Genes; Genetic Engineering; Hematological Disease; Hematopoietic stem cells; In Vitro; Individual; Kinetics; Lateral; Lead; Leukocytes; Life; Lymphocyte; Mediating; Modeling; Not Defined; Numbers; Operative Surgical Procedures; Pathway interactions; Process; Proteins; Regulation; Series; Staging; Statistical Models; Stem cells; Study models; System; Systems Biology; T-Cell Development; T-Lymphocyte; Testing; Time; base; cell type; developmental genetics; experimental analysis; human disease; insight; network models; precursor cell; prevent; programs; research study

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：发育是一个矢量过程，必然受到多个基因及其调控相互作用的控制。迄今为止已破译的少数发育遗传调控网络揭示了胚胎发育涉及大型、多层网络、非线性调控过程以及由多种前馈、横向和反馈相互作用介导的复杂动态。由于这些特征，只有在系统生物学的框架内才能正确理解发育。需要理解的一个特别重要的模型是血细胞发育。所有血细胞都是由造血干细胞 (HSC) 在整个生命过程中通过严格调控的发育过程不断生成的，而在许多主要血液疾病中，这些发育过程会被破坏。每种不同血细胞类型的发育前体不仅取决于它们获得成熟特征，还取决于它们保留替代血细胞分化途径的程度。 HSC 分化出的 T 淋巴细胞是一个系统，可以异常清晰地了解发育选择的时间进程及其所经历的中间阶段。 T谱系命运选择基于调节输入之间的长期竞争，前体细胞只有在许多细胞周期后才能解决。该项目将利用 T 细胞发育的计算和实验研究来破译环境和内在调节输入如何整合，以驱动哺乳动物血液干细胞在不同的白细胞发育命运中进行选择，并实现从可塑性到承诺的转变。 Hamid Bolouri 将领导该项目的计算部分。他的小组将开发计算方法，用于预测和整合蛋白质-蛋白质和蛋白质-DNA 相互作用与基因扰动数据，以生成一系列替代基因网络假设。他的团队将使用正式的统计模型选择来完善网络运行的动力学模型。这些计算预测将指导实验程序并解释其生成的数据。艾伦·罗森伯格将领导该项目的实验部分。 Rothenberg 小组将利用体外分化系统、基因特异性扰动和定量多基因表达数据来剖析指导 T 细胞从干细胞中出现的调控网络关系。还将跟踪单个细胞的这一过程的动力学。在扰动中测试的具体假设将通过与 Bolouri 小组所做的建模研究的持续互动进行迭代完善。血细胞在整个生命过程中都是由干细胞产生的，许多人类疾病的根源都是血细胞发育过程的复杂调节紊乱。 T 细胞发育具有许多特征，使其成为研究控制细胞命运选择的机制以及引导未成熟细胞远离异常命运的严格调节机制的优秀系统。通过计算模型和实验分析之间的对话，我们将解释使 T 细胞发育稳健的调控网络，为预防疾病的机制提供新的见解。