Establishing a Potential and Flux Landscape Theory for Stem Cell Fate Decision Making of Differentiation and Reprograming

决策对细胞功能至关重要，并通过许多潜在的细胞过程实现，如信号传导、基因调控、病毒、细菌、酵母、后生动物和哺乳动物的发育和分化。了解细胞分化和重编程的决策过程，从多能干细胞或祖细胞状态到成熟细胞再到成熟细胞的生物学过程，不仅对揭示其潜在机制至关重要，而且对组织再生的实践也至关重要。尽管在这一领域取得了巨大的努力和进展，但干细胞命运决策仍然面临着重大挑战：(1)如何定义细胞状态和细胞命运，如何揭示决策的物理机制和动力学；(2)如何量化命运决策过程的分化和重编程路径；(3)如何识别决定细胞命运的关键因素；(4)表观遗传学、微rna和细胞间通讯对细胞分化和重编程的影响；(5)该研究与组织再生的重编程和实践有何关系。解决这些问题是本项目的目标，特别是干细胞命运决策过程的量化，由于缺乏定量物理理论作为基础，迄今为止仍然很困难。该项目将通过发展干细胞决策的物理景观和通量理论来应对这些挑战。有三个目标。在目标1中，PI将发展干细胞分化和重编程的景观和通量理论，并量化细胞状态，动态速率，动力学路径和干细胞决策过程的关键调控。在Aim 2中，PI将把该理论应用于胚胎发育中干细胞分化的核心基因网络。他将进一步探讨分化和重编程的机制。他将通过建模和实验探索表观遗传学通过缓慢调节结合对分化和重编程的影响。在Aim 3中，PI将把这一理论应用于胚胎发育中涉及的干细胞分化和重编程的现实网络。他将量化潜在的景观地形，动态速率和路径，考虑到表观遗传学，微rna和细胞-细胞通讯。他还将预测干细胞命运的关键基因和调控，以及重编程所必需的决策过程，这可以通过实验来验证。这在重编程和组织工程方面具有潜在的应用前景。该项目由物理系的生命系统物理学项目和分子与细胞生物科学系的系统与合成生物学集群共同支持。

Decision making is essential for cell functions and realized through many underlying cellular processes, such as signaling, gene regulation, the development and differentiation in viruses, bacteria, yeast, metazoans, and mammals. Understanding the cell decision making for differentiation and reprograming, the biological process from a multi-potent stem or progenitor state to a mature cell and back, is crucial not only for uncovering the underlying mechanisms but also for the practice of tissue regeneration. Despite significant efforts and progress made in this field, there are still major challenges in the stem cell fate decision making: (1) how to define the cell states and cell fates and how to uncover the physical mechanism and dynamics of decision making; (2) how to quantify the differentiation and reprograming paths for the fate decision process; (3) how to identify key factors determining the cell fates; (4) what are the effects of epigenetics, micro RNAs and cell-cell communications on differentiation and reprograming; and (5) how is the study related to the reprograming and practice of tissue regeneration. Addressing these issues is the goal of this project and specifically the quantification of the stem cell fate decision making process, which is still difficult so far due in part to the lack of a quantitative physical theory as the foundation.This project will meet these challenges through developing a physical landscape and flux theory for stem cell decision making. There are three aims. In Aim 1 the PI will develop the landscape and flux theory of stem cell differentiation and reprograming, and quantify cell states, dynamical rates, kinetic paths, and key regulations of the stem cell decision making process. In Aim 2, the PI will apply the theory to a core gene network of the stem cell differentiation in embryo development. He will further explore the mechanism of differentiation and reprograming. He will explore the effects of epigenetics through slow regulatory binding on differentiation and reprograming by modeling and experiments. In Aim 3, the PI will apply this theory to a realistic network for stem cell differentiation and reprograming involved in embryo development. He will quantify the underlying landscape topography, dynamical rates and paths, taking into consideration epigenetics, micro RNAs and cell-cell communications. He will also predict key genes and regulations for the stem cell fates and decision making process essential for reprogramming, which can be verified from experiments. This has potential applications on reprograming and tissue engineering.This project is being jointly supported by the Physics of Living Systems program in the Division of Physics and the Systems and Synthetic Biology Cluster in the Division of Molecular and Cellular Biosciences.