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

这一行动为NSF 2021财年生物学博士后研究奖学金提供了资金，综合研究调查了支配基因组、环境和表型之间相互作用的生命规则。该奖学金支持研究员的研究和培训，这些研究员将以创新的方式为生活规则领域做出贡献。生命中最基本的规则之一是“中心教条”，它声称DNA是蛋白质的遗传密码。随着数以千计的蛋白质的活性已经被确定，下一个生命规则需要定义这些重叠的蛋白质信号如何分解来控制细胞和构建组织。这项研究旨在了解细胞是如何使用多条冗余路径相互交谈并实现特定结果的。简而言之，这项研究将扩展已确立的中央教条，并加强对细胞信号网络如何整合的科学理解。同时，这项研究将推进空间转录学和有机工程的科学技术，在疾病模型和药物毒性测试中具有深远的应用。这项研究还将通过为华盛顿大学周边社区中未被充分代表的少数族裔提供指导和外展机会来扩大STEM的参与。下一条生活规则应该确定众多细胞信号级联如何实现可预测的表型。以再生肝为模型表型，这项研究将确定驱动这一表型的生物信号及其起源的细胞间来源。将使用单细胞RNA测序和空间转录组学来研究人肝组织和生物工程人肝移植，以创建肝细胞信号网络的“蓝图”。这些网络将通过工程设计的新型人类肝脏有机化合物共培养模型在体外重建。为了模拟细胞：自然组织中的细胞相互作用，人类原代肝上皮类有机物质将与它们的体内邻居内皮细胞和成纤维细胞一起培养。最后，将在体外和体内移植物中检测共培养的有机化合物中的细胞信号网络，以证明它们参与肝脏再生。将探索个体信号网络的组成部分，以确定它们对肝脏再生表型的贡献，并制定预测生命的规则。这些研究成果将通过教学、会议演示和出版等培训机会进行交流。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势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.