NSF Postdoctoral Fellowship in Biology FY 2021: Translating transcriptome to phenome: defining intercellular signaling landscapes of the liver

该行动资助2021财年NSF生物学博士后研究奖学金，研究基因组，环境和表型之间相互作用的生命规则的综合研究。该奖学金支持将以创新方式为《生活规则》领域作出贡献的研究员的研究和培训。生命最基本的规则之一是“中心法则”，它指出DNA是蛋白质的遗传密码。随着数千种蛋白质的活性被确定，生命的下一个规则需要定义这些重叠的蛋白质信号如何控制细胞和构建组织。这项研究的目的是了解细胞如何使用多个冗余途径相互交谈并达到特定的结果。简而言之，这项研究将扩展既定的中心教条，并加强对细胞信号网络如何整合的科学理解。同时，这项研究将推动空间转录组学和类器官工程的科学技术，在疾病模型和药物毒性测试方面具有深远的应用。这项研究还将通过为华盛顿大学周围社区中代表性不足的少数民族提供指导和外展机会，扩大STEM的参与。生命的下一个规则应该是确定无数细胞信号级联如何实现预测性表型。使用再生肝脏作为模型表型，本研究将确定驱动该表型的生物信号及其起源的细胞间来源。人类肝脏组织和生物工程人类肝脏移植将使用单细胞RNA测序和空间转录组学来创建肝细胞信号网络的“蓝图”。这些网络将通过工程化的新型人类肝脏类器官共培养模型在体外重建。为了模拟天然组织中细胞间的相互作用，人类原代肝上皮类器官将与其在体内的邻居内皮细胞和成纤维细胞一起培养。最后，将在体外和体内共培养的类器官移植物中检查细胞信号网络，以证明它们参与肝脏再生。个体信号网络的组成部分将被探索，以确定它们对肝脏再生表型的贡献，并制定一个生命的预测规则。这些研究成果将通过教学、会议演讲和出版物等培训机会进行交流。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

This action funds an NSF Postdoctoral Research Fellowship in Biology for FY 2021, Integrative Research Investigating the Rules of Life Governing Interactions Between Genomes, Environment and Phenotypes. The fellowship supports research and training of the Fellow that will contribute to the area of Rules of Life in innovative ways. One of the most fundamental rules of life is the “central dogma” and states that DNA is the genetic code for proteins. As the activity of thousands of proteins have been identified, the next rule of life needs to define how these overlapping protein signals resolve to control cells and build tissues. This research aims to understand how cells use multiple redundant pathways to talk to one another and achieve a particular outcome. In short, this research will expand upon the established central dogma and enhance scientific understanding of how cell signaling networks are integrated. While doing so, this research will advance scientific technology in spatial transcriptomics and organoid engineering with far reaching applications in disease models and drug toxicity testing. This research will also broaden the participation in STEM through mentorship and outreach opportunities for underrepresented minorities in the University of Washington surrounding community.The next rule of life should establish how numerous cell signaling cascades achieve a predictive phenotype. Using the regenerating liver as a model phenotype, this research will determine the biological signals and their originating intercellular sources that drive that phenome. Human liver tissue and bioengineering human liver grafts will be studied using single cell RNA sequencing and spatial transcriptomics to create a ‘blueprint’ of liver cell signaling networks. These networks will be reconstructed in vitro through an engineered novel human liver organoid coculture model. To mimic the cell:cell interactions in native tissue, human primary liver epithelial organoids will be cultured alongside their in vivo neighbors, endothelial and fibroblast cells. Finally, cell signaling networks will be examined within the cocultured organoids in vitro and in in vivo grafts to prove their involvement in liver regeneration. Components of individual signaling networks will be probed to determine their contribution to the liver regeneration phenotype and develop a predictive rule of life. These research findings will be communicated through training opportunities such as teaching, conference presentations and publications.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.