CAREER: Mechanisms Underlying Temporal Integration of BMP Signaling in Cell Fate Decisions

职业：细胞命运决定中 BMP 信号时间整合的潜在机制

• 批准号: 2340659
• 负责人: Idse Heemskerk
• 金额: $ 181.33万
• 依托单位: Regents of the University of Michigan - Ann Arbor
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2024
• 资助国家: 美国
• 起止时间: 2024-03-01 至 2029-02-28
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2340659&HistoricalAwards=false
• 关键词: CAREER; Mechanisms; Underlying; Temporal; Integration

The Heemskerk lab previously showed that for the cell signal called Bone Morphogenetic Protein (BMP), cells add up the amount of signal they see over time to decide whether to specialize to one specific cell type. This project will combine experimental and computational methods to understand how cells keep track of the past signaling and determine if later specialization events to other cell types follow the same rules. Multiple undergraduate and graduate students will be trained to perform this research, preparing them for careers that increasingly demand integration of computational and experimental approaches to tackle scientific problems. A collaboration with the University of Michigan Museum of Natural History (UMMNH) will communicate stem cell research and its societal benefits to diverse audiences. To reach younger audiences, the researchers will partner with the UMMNH to develop a curriculum for teaching middle school students in underrepresented communities from metro-Detroit, as well as a small year-long exhibit and additional outreach activities at the museum. To reach adults, the research team will discuss stem cell research and human development in public Science Café events and expand a course module for graduate students to teach the methods applied in this project.BMP is a quintessential signaling molecule that plays a conserved role in early development. This project uses human pluripotent stem cells (hPSCs) as an in vitro model to address the mechanisms by which BMP controls cell fate decisions in early human development. Preliminary work revealed that differentiation of hPSCs to amnion-like cells does not depend on the level or duration of signaling separately, but only on the time integral, i.e. the total amount of signaling over time. This is contrary to the common assumption that signaling level is the main determinant of cell response and implies different molecular mechanisms for signal processing. A preliminary screen yielded genes whose levels are linearly related to the time integral of signaling, providing a simple potential mechanism, but how these genes are regulated by BMP and how they in turn control other genes is unclear. We also do not know if BMP integration is conserved across different contexts. Therefore, this project aims to 1) reveal the mechanisms underlying temporal integration of BMP signaling during amnion-like differentiation, 2) understand how signal response depends on the initial state of the cell, 3) determine if these mechanisms are conserved across different cell fate decisions and species. Together, this work will yield a more profound understanding of BMP signaling in pluripotent stem cells and contribute to revealing general principles by which dynamic signaling controls cell fate, enabling more reproducible stem cell differentiation in vitro.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.

Heemskerk 实验室此前表明，对于称为骨形态发生蛋白 (BMP) 的细胞信号，细胞会随着时间的推移将它们看到的信号量相加，以决定是否专门针对一种特定的细胞类型。该项目将结合实验和计算方法来理解。细胞如何跟踪过去的信号传导并确定其他细胞类型的后续专业化事件是否遵循相同的规则将培训多名本科生和研究生进行这项研究，为他们的职业做好准备，这些职业越来越需要整合计算和实验方法。与解决科学问题。密歇根大学自然历史博物馆 (UMMNH) 将向不同的受众宣传干细胞研究及其社会效益，为了吸引年轻受众，研究人员将与 UMMNH 合作开发一门课程，为都市中代表性不足的社区的中学生提供教学。底特律，以及博物馆的为期一年的小型展览和其他外展活动，为了接触成年人，研究小组将在公共科学咖啡馆活动中讨论干细胞研究和人类发展，并为研究生扩展一个课程模块，以教授这些知识。在此应用的方法项目.BMP 是一种典型的信号分子，在早期发育中发挥保守作用。该项目使用人类多能干细胞 (hPSC) 作为体外模型来解决 BMP 在人类早期发育中控制细胞命运决定的机制。研究表明，hPSC 向羊膜样细胞的分化并不单独取决于信号传导的水平或持续时间，而仅取决于时间积分，即随时间变化的信号传导总量。这与常见的假设相反。信号传导水平是细胞反应的主要决定因素，并且意味着信号处理的不同分子机制。初步筛选产生的基因，其水平与信号传导的时间积分线性相关，提供了一个简单的潜在机制，但这些基因是如何受 BMP 调节的。我们也不知道 BMP 整合在不同环境中是否保守，因此，该项目旨在 1) 揭示羊膜样分化过程中 BMP 信号时间整合的机制。了解信号响应如何取决于3) 确定这些机制在不同细胞命运决定和物种中是否保守，这项工作将产生对多能干细胞中 BMP 信号传导的更深刻理解，并有助于揭示动态变化的一般原理。信号传导控制细胞命运，从而在体外实现更可重复的干细胞分化。该奖项反映了 NSF 的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。