Measuring and modeling the dynamics ofpatterning in human stem cells

测量和模拟人类干细胞模式的动态

基本信息

批准号：
10734567
负责人：
Sharad Ramanathan
金额：
$ 34.01万
依托单位：
HARVARD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-11 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10734567
关键词：
Address Agreement Anterior Automobile Driving Biomedical Engineering Buffers CRISPR interference Cell Line Cells Complex Data Defect Development Developmental Biology Embryo Ethics Etiology Feedback Fetal Tissues Fibroblast Growth Factor Gene Expression Gene Expression Profile Genes Genetic Goals Growth Human Human Development Image In Situ In Vitro Ligands Maintenance Measures Mesoderm Mesoderm Cell Methods Microscopy Modeling Molecular Biology Monitor Morphogenesis Morphology Mus Neural tube Neurons Noise Organoids Paraxial Mesoderm Pattern Predisposition Process Proliferating Proteins Reporter Reproducibility Research Role Signal Pathway Signal Transduction Source Spinal Cord Spinal Dysraphism System Tail Testing Tissues Transcriptional Regulation Tretinoin Undifferentiated Vertebrates WNT Signaling Pathway Work cell type developmental disease dynamic system embryo tissue embryonic stem cell experimental study gene regulatory network human disease human model human stem cells image processing in situ sequencing in utero in vitro Model in vivo insight knock-down mathematical model model organism morphogens neural novel optogenetics predictive modeling prevent progenitor receptor scoliosis self-renewal single cell sequencing somitogenesis spatiotemporal stem cells tool transcription factor transcriptome sequencing

项目摘要

Abstract The long-term goal of this project is to understand how cells sense and process signals to make fate decisions and pattern into complex tissues, both during normal human development and in developmental diseases. How tissues of the embryo pattern and undergo morphogenesis is a fundamental question in developmental biology. This application will address the question in the context of the axial elongation of the human embryo during development, during which it breaks anterior-posterior (A-P) symmetry, forms a tailbud posteriorly, and elongates along the A-P axis. The progenitors in the tail bud proliferate to drive this extension and further differentiate to give rise to neural and mesodermal cell types. This proposal aims to understand how axial elongation is driven and how the progenitor cells in the tailbud maintain a self-sustaining pool, even as they differentiate into neural and mesodermal cells. Since the mechanisms underlying human axial elongation and patterning are not shared between other vertebrates, the generalizability of results from model organisms to humans remains unknown. While ethical reasons necessitate the use of in vitro models of human development, the large variability in such organoid systems has been a critical barrier. Preliminary work overcame this barrier to strikingly and reproducibly model human axial morphogenesis and patterning by developing an organoid system that elongates to generate the posterior neural tube and flanking paraxial mesoderm. Using this powerful system, the proposal seeks to answer two fundamental questions associated with this process: first, how morphogen signals break A-P symmetry and stably drive self-sustaining axial extension along a single axis. The goal is to uncover the underlying dynamical system that is activated to drive self-sustaining axial elongation and to understand how this system buffers against noise so as not to be susceptible to dynamical instabilities, for example, leading to branched or multiple axes. The second is to determine the dynamical system governing the maintenance of a proliferating pool of progenitors in the tailbud throughout axial elongation, even as they are driven to differentiate into neural and mesodermal tissues. The proposal brings together methods to infer and measure spatiotemporal profiles of gene expression; compare these profiles with other model organisms to determine similarities and differences in gene expression patterns driving axial elongation, and Bayesian ensemble modeling to build predictive models of the GRN driving axial elongation and experimental tools to test model predictions. The proposal will allow us to achieve a quantitative understanding of the dynamics across scales, from intracellular signaling and transcriptional regulation to cellular rearrangement to tissue-level axial extension made possible by new human stem cell lines, imaging, image processing, statistical inference, mathematical modeling, and bioengineering tools, to provide insights into principles governing human axial elongation. The ability to build and test quantitative predictive models of human axial extension will open novel avenues to understanding the mechanisms underlying human diseases.

抽象的该项目的长期目标是了解细胞如何感知和处理信号以做出命运决定并在正常人类发育和发育疾病期间形成复杂组织的模式。胚胎组织的模式和形态发生是发育中的一个基本问题生物学。该应用将解决人类胚胎轴向伸长的问题在发育过程中，它打破前后（A-P）对称性，在后面形成尾芽，并且沿 A-P 轴伸长。尾芽中的祖细胞增殖以驱动这种延伸并进一步分化产生神经细胞和中胚层细胞类型。该提案旨在了解轴向伸长是驱动的，以及尾芽中的祖细胞如何维持一个自我维持的池，即使它们分化为神经细胞和中胚层细胞。由于人类轴向伸长的机制和模式在其他脊椎动物之间不共享，模型生物的结果具有普遍性人类仍然未知。虽然伦理原因需要使用人类体外模型开发中，此类类器官系统的巨大变异性一直是一个关键障碍。初步工作克服了这一障碍，以惊人且可重复的方式模拟人类轴向形态发生和通过开发类器官系统来形成图案，该系统可以伸长以生成后神经管和侧翼近轴中胚层。该提案旨在利用这个强大的系统来回答两个基本问题与这个过程相关的：第一，形态发生素信号如何打破A-P对称性并稳定驱动自持沿单个轴线的轴向延伸。目标是揭示被激活的潜在动力系统驱动自持轴向伸长，并了解该系统如何缓冲噪音，以免被容易受到动态不稳定的影响，例如，导致分支轴或多轴。第二个是确定控制尾芽中祖细胞增殖池维持的动力系统在整个轴向伸长过程中，即使它们被驱动分化为神经和中胚层组织。这该提案汇集了推断和测量基因表达时空概况的方法；比较将这些图谱与其他模型生物体进行比较，以确定基因表达模式的相似性和差异驱动轴向伸长率和贝叶斯集成建模，以构建 GRN 驱动轴向的预测模型用于测试模型预测的伸长率和实验工具。该提案将使我们能够实现定量了解跨尺度的动态，从细胞内信号传导和转录调控到新的人类干细胞系、成像、图像处理、统计推断、数学建模和生物工程工具，以提供见解纳入控制人体轴向伸长的原则。建立和测试定量预测模型的能力人类轴向延伸将为理解人类疾病的机制开辟新途径。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Controlling human organoid symmetry breaking reveals signaling gradients drive segmentation clock waves.

控制人体器官对称性破坏揭示了信号梯度驱动分段时钟波。

DOI：
发表时间：
2023-02-02
期刊：
影响因子：
64.5
作者：
Yaman, Yusuf Ilker;Ramanathan, Sharad
通讯作者：
Ramanathan, Sharad

Mouse embryo geometry drives formation of robust signaling gradients through receptor localization.

小鼠胚胎几何形状通过受体定位驱动强大的信号梯度的形成。

DOI：
发表时间：
2019-10-04
期刊：
影响因子：
16.6
作者：
Zhang, Zhechun;Zwick, Steven;Loew, Ethan;Grimley, Joshua S;Ramanathan, Sharad
通讯作者：
Ramanathan, Sharad

Controlling organoid symmetry breaking uncovers an excitable system underlying human axial elongation.

控制类器官对称性破坏揭示了人类轴向伸长背后的可兴奋系统。

DOI：
发表时间：
2023-02-02
期刊：
影响因子：
64.5
作者：
Anand, Giridhar M;Megale, Heitor C;Murphy, Sean H;Weis, Theresa;Lin, Zuwan;He, Yichun;Wang, Xiao;Liu, Jia;Ramanathan, Sharad
通讯作者：
Ramanathan, Sharad