EAGER: Modeling Multiscale Control of Liver Regeneration

肝病每年影响数以百万计的人。肝病的治疗通常需要肝移植，因为在许多情况下，受损的肝组织无法再生。更好地了解肝组织是如何更新和修复的，将提高开发未来干预措施的能力。由于相邻的细胞不一定以相同的方式做出反应，理解组织生理学常常变得复杂。旨在对数百到数千个单细胞进行高通量分子分析的新兴技术和分析方法，使人们能够前所未有地了解细胞功能状态的异质性、层次性和复杂性。多尺度建模是一种可以帮助理解可观察到的细胞行为变化的工具，因此本研究项目正在开发一种新的多尺度建模框架，该框架利用了可以从这些单细胞数据集中获得的关于细胞功能的深入信息。这个建模框架从分子尺度到组织尺度，以增强获得的生理学和病理生理学知识。虽然这个模型的输出将支持对肝脏损伤组织反应的更好的理解和操作，但它也可能适用于理解其他组织。研究团队正在将从高中到研究生院的各级学生纳入这个项目，以激发他们对科学研究的热情，并为他们提供职业发展机会。该项目的中心创新想法是通过开发细胞功能状态和状态转换的模型来实现新型单细胞数据集的全部潜力，以连接分子和组织尺度。该团队正在开发拟议的多尺度建模框架，以了解控制组织对损伤的协调反应的控制原则。这种方法涉及免疫细胞、间质细胞、内皮细胞和上皮细胞的细胞功能状态的显式计算，以及驱动状态转换的假定的分子过程，广泛适用于多种组织修复方案。该团队将重点放在肝脏再生的过程上，作为一个使能试验台，以便充分开发、微调和说明多尺度建模方法，以获得更广泛的应用和实用。

Liver disease affects millions of individuals each year. Treatment for liver disease often requires a liver transplant due to the inability of damaged liver tissue to regenerate in many cases. A better understanding how liver tissue is renewed and repaired will improve the ability to develop future interventions. Understanding tissue physiology is often complicated by the fact that cells next to each other do not necessarily respond the same manner. Emerging technologies and analysis methods aimed at high-throughput molecular assays of hundreds-to-thousands of single cells have enabled an unprecedented view of the heterogeneity, hierarchy and complexity of cellular functional states. Multiscale modeling is one tool that can aid in understanding the variation in observable cellular behavior, so this research project is developing a novel multiscale modeling framework that takes advantage of the in-depth information on cellular function that can be obtained from these single cell data sets. This modeling framework bridges from the molecular scale to the tissue scale to enhance knowledge gained about physiology and pathophysiology. While the outputs from this model will support improved understanding and manipulation of tissue response to injury in the liver, it will likely be applicable to understanding other tissues as well. The research team is integrating students of all levels, from high school through graduate school, in this project in order to excite them about scientific research and to provide them with professional development opportunities. The central innovative idea of this project is to realize the full potential of the novel single cell data sets by developing models of cellular functional states and state transitions to bridge the molecular and tissue scales. The team is developing the proposed multiscale modeling framework in the context of understanding the control principles governing the coordinated tissue response to injury. This approach involves explicit accounting of cellular functional states of immune, stromal, endothelial and epithelial cells, and putative molecular processes driving the state transitions, with broad applicability to multiple tissue repair scenarios. The team is focusing on the process of liver regeneration as an enabling testbed in order to fully develop, fine tune and illustrate the multiscale modeling approach for broader application and utility.