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 Lab先前表明，对于称为骨形态发生蛋白（BMP）的细胞信号，细胞会增加他们随着时间的推移所见的信号量，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，以了解细胞如何跟踪过去的信号传导，并确定以后对其他细胞类型的专业事件是否遵循相同的规则。多个本科生和研究生将接受培训以进行这项研究，为他们的职业做好准备，这些职业越来越多地要求将计算和实验方法整合起来解决科学问题。与密歇根大学自然历史博物馆（UMMNH）的合作将传达干细胞研究及其对潜水受众的社会利益。为了吸引年轻的观众，研究人员将与UMMNH合作，开发一门课程，以教授来自Metro-Detroit的代表性不足社区的中学生，以及为期一年的小展览和博物馆的其他外展活动。为了吸引成年人，研究小组将讨论公共科学咖啡厅活动中的干细胞研究和人类发展，并扩展了一个课程模块，供研究生教授该项目中应用的方法。BMP是一种典型的信号分子，在早期发展中起着保守的作用。该项目使用人类多能干细胞（HPSC）作为一种体外模型，以解决BMP控制早期人类发育中细胞脂肪决策的机制。初步工作表明，HPSC与羊膜样细胞的分化不取决于单独信号的水平或持续时间，而仅取决于时间积分的时间积分，即信号的总数随时间的时间。这与常见的假设形成鲜明对比：信号传导水平是细胞反应的主要确定，并暗示了信号处理的不同分子机制。初步屏幕产生的基因与信号的时间相关的水平线性相关，提供了一种简单的潜在机制，但是这些基因如何受BMP调节，以及它们如何控制其他基因尚不清楚。我们也不知道是否在不同上下文中配置了BMP集成。因此，该项目的目的是1）揭示在羊膜样分化过程中BMP信号传导暂时整合的机制，2）了解信号响应如何取决于细胞的初始状态，3）确定这些机制是否在不同的细胞脂肪决策和物种中保存。这项工作共同对多能干细胞中的BMP信号传导产生更深刻的了解，并有助于揭示动态信号控制细胞命运的一般原则，从而在体外可以更可重复可重复的干细胞分化。该奖项反映了NSF的法规任务，并通过使用基金会的知识效果和广泛的影响来诚实地通过评估来诚实地进行了评估，并诚实地审查了Crositia和广泛的影响。