CAREER: Measuring and Modeling Non-canonical Wnt Signaling in Regulation of Cell State

该项目旨在提供细胞间通讯的见解，细胞间通讯在胚胎发育过程中形成组织和器官以及不同身体部位的组织中起着至关重要的作用。细胞如何沟通和控制这些基本的生物过程是高度复杂和动态的，它们的行为很难从单个部分的知识来预测。因此，问题出现了，我们应该如何分析和理解这种复杂性，以及哪种测量技术将被证明是最有用的。最近，一些用于收集大规模数据集的高通量方法，特别是那些涉及基因表达的方法，为基于数据驱动系统生物学的项目打开了大门。然而，研究许多相互作用，即使是在一个紧密相连的网络中，也是很强大的，但往往很难只见树木不见森林。大多数情况下，系统生物学家依靠数学和计算模型来分析大规模数据集，并使用这些模型来取得科学突破。为了在实验和计算方法上激励和培养下一代科学家，该项目将为来自不同背景的本科生提供一个机会，让他们学习基于细胞生物学的前沿实验和计算方法，以从大规模定量实验数据中制定、简化和提取关键信息。针对高中教师的“细胞决策”概念的实践培训和课程计划相结合，将进一步在高中生中推广数据驱动生物学。从事该项目的研究生和博士后将整合实验和数学建模技术，这些技术可以应用于生物学的广泛领域。这一定量研究主题将通过对高中生的指导和与当地社区的公众参与活动来推进。上皮-间质转化（epithelial-mesenchymal transition， EMT）是复杂组织中细胞分化的主要机制。在EMT过程中，上皮细胞通过改变其形态、细胞结构、粘附和迁移能力来获得间充质特性。包括tgf - β和Wnt在内的几种生长因子已被证明在胚胎发育以及正常细胞和转化细胞中都能触发EMT。然而，对于这些不同的因素如何协同诱导上皮细胞的EMT或成纤维细胞的转分化的机制和综合理解仍然缺乏。该项目的目标是全面了解Wnt和tgf - β通路如何控制EMT和细胞迁移的基本细胞生物学和发育过程。该研究项目将揭示Wnt信号驱动EMT和促进细胞迁移的机制，并确定Wnt和tgf - β信号之间的合作是否对于EMT是必要的。该项目还将提供生化描述，以确定Wnt途径中的蛋白质如何与tgf - β信号相互作用和相互连接，并确定这些连接如何在上皮细胞进行转分化时发生变化。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 project aims to provide insights into cell-to-cell communication that play a crucial role in forming tissues and organs and the organization of different body parts during embryonic development. How cells communicate and govern these fundamental biological processes are highly complex and dynamic, and their behavior is very difficult to predict from knowledge of the individual parts. Therefore, the question arises how we should analyze and understand such complexity and which measurement technologies will prove most useful. Recently, several high-throughput approaches for collecting large-scale datasets, particularly those involving gene expression, have unlocked the door to data-driven systems biology-based projects. However, studying many interactions, even in a closely interconnected network, is powerful, but it is often hard to see the forest for the trees. Most often, system biologists rely on mathematical and computational models to analyze large-scale datasets and use these models to make scientific breakthroughs. To inspire and train the next generation of scientists in both experimental and computational approaches, this project will provide an opportunity for undergraduate students from diverse backgrounds to learn both cutting-edge cell biology-based experimentation and computational methods for formulating, simplifying, and extracting critical information from large-scale quantitative experimental data. A combination of hands-on training and lesson plans on the concept of 'cellular decision-making' for high school teachers will further promote data-driven biology among high school students. The graduate students and postdoctoral fellows working on this project will integrate experimental and mathematical modeling techniques that can be applied to broad areas of biology. This quantitative research theme will be carried forward by mentorship to high school students and through public engagement activities with the local community. The epithelial-mesenchymal transition (EMT) is a central mechanism for diversifying the cells found in complex tissues. During EMT, epithelial cells adopt mesenchymal properties by altering their morphology, cellular architecture, adhesion, and migratory capacity. Several growth factors, including TGF-beta and Wnt, have been shown to trigger the EMT in both embryonic development as well as normal and transformed cells. However, a mechanistic and integrated understanding of how these various factors cooperate to induce the EMT in epithelial cells or transdifferentiation in fibroblast is still lacking. The goal of this project is to develop an integrated understanding of how Wnt and TGF-beta pathways control fundamental cell biological and developmental processes of EMT and cell migration. The research project will reveal mechanistic insights into how Wnt signaling drives EMT and promotes cell migration, and determine whether cooperation between Wnt and TGF-beta signaling is necessary for EMT. The project will also provide a biochemical portrait to determine how proteins in the Wnt pathway interact and interconnect with TGF-beta signaling and determine how these connections change as epithelial cells undergo transdifferentiation.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.