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实验室先前的研究表明，对于骨形态发生蛋白（BMP）的细胞信号，细胞会随着时间的推移，将它们看到的信号数量加起来，以决定是否分化为一种特定的细胞类型。该项目将结合实验和计算方法来了解细胞如何跟踪过去的信号，并确定后来对其他细胞类型的特化事件是否遵循相同的规则。多名本科生和研究生将接受这项研究的培训，为他们的职业生涯做好准备，这些职业越来越需要综合计算和实验方法来解决科学问题。与密歇根大学自然历史博物馆（UMMNH）的合作将向不同的受众传播干细胞研究及其社会效益。为了吸引更年轻的观众，研究人员将与UMMNH合作，为底特律大都会代表性不足的社区的中学生制定一套课程，并在博物馆举办为期一年的小型展览和额外的推广活动。为了让成年人了解干细胞研究和人类发育，研究小组将在公共科学会议上讨论干细胞研究和人类发育，并扩大研究生课程模块，教授该项目中应用的方法。bmp是一种典型的信号分子，在早期发育中起着保守的作用。该项目使用人类多能干细胞（hPSCs）作为体外模型来解决BMP在早期人类发育中控制细胞命运决定的机制。初步研究表明，造血干细胞向羊膜样细胞的分化不依赖于信号传导的水平或持续时间，而只依赖于时间积分，即信号传导随时间的总量。这与通常认为信号水平是细胞反应的主要决定因素的假设相反，并暗示信号处理的不同分子机制。初步筛选得到的基因水平与信号的时间积分线性相关，提供了一种简单的潜在机制，但这些基因如何受BMP调节以及它们如何反过来控制其他基因尚不清楚。我们也不知道BMP的整合是否在不同的环境中是保守的。因此，本项目旨在1)揭示羊膜样分化过程中BMP信号的时间整合机制，2)了解信号反应如何依赖于细胞的初始状态，3)确定这些机制是否在不同的细胞命运决定和物种中保守。总之，这项工作将产生对多能干细胞中BMP信号的更深刻的理解，并有助于揭示动态信号控制细胞命运的一般原理，使体外干细胞分化更具可重复性。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。