Understanding and rewiring cellular behavior with synthetic biology approaches

用合成生物学方法理解和重新连接细胞行为

基本信息

批准号：
10662938
负责人：
Zara Weinberg
金额：
$ 12.5万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-03 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10662938
关键词：
Advocacy Behavior Biological Models Biology Biosensor Cell Maintenance Cell Shape Cell Therapy Cell model Cell physiology Cells Cellular biology Computer Models Cyclic AMP Data Development Developmental Biology Disease Educational process of instructing Embryo Engineering Environment Epiblast Fishes Future Genetic Genetic Transcription Genomics Goals Health Hour Human In Vitro Intelligence Ions Justice Maintenance Mediating Medicine Mentors Mentorship Methods Mitogens Modeling Modification Morphology Mus Neurosciences Pathway interactions Phosphotransferases Physiological Physiology Positioning Attribute Production Proliferating Proteomics Regulation Reporter Research Role Signal Pathway Signal Transduction Specificity Stimulus System Tissues Training Transgenes Whole Organism Work Zebrafish cell behavior cell type cellular engineering embryonic stem cell epigenomics equity, diversity, and inclusion experience frontier human disease information processing insight non-genetic novel novel therapeutics optogenetics pluripotency predictive modeling prevent programs response screening small molecule spatiotemporal stem cells synthetic biology tool transcription factor transcriptomics

项目摘要

PROJECT SUMMARY Human physiology depends on precise cellular responses to environmental signals. Specificity in responding to environmental signals is achieved through specific proteomic, transcriptomic, epigenomic, and non-genetic cell states. In physiological states, healthy cells function in harmony with their surrounding tissues, performing specific functions in response to environmental stimuli. In disease, dysregulation of cell state can prevent cells from producing necessary responses and lead to proliferation independent of physiological context. Understanding how cell state drives cell function is essential for understanding tissue function in health and disease, and is required for engineering cell therapies capable of specific behaviors encoded by their target environments. Despite decades of research into single cell biology, we still don't understand the fundamental principles that connect cell state with specificity in cellular responses to their environment In my proposed research, I will use synthetic biology tools to quantitatively probe the connection between cell state and signaling specificity. My proposed work will provide insight into how cells of different types achieve unique responses to their environments and will generate computational models that can be used to engineer cellular behavior. To investigate how cells of different types uniquely respond to the same signal, I will use optogenetics to perturb the model signal cAMP in candidate cell types of the early mouse embryo and in an unbiased screen in developing zebrafish. My studies in mouse embryonic stem cells will serve as a proof of principle for controlling cell type through intracellular signaling and for rewiring cellular responses with genetic expression programs. My work in zebrafish will result in a predictive model that can be used to infer a given cell's unique response to a stimulus using only transcriptional data from that cell. Throughout this work, I will focus on generating interpretable computational models that can be used in the future to engineer cellular behavior. I will achieve the above work through synthesizing my previous training in neuroscience, cell signaling, and applied synthetic biology with proposed training in developmental biology, genomics, quantitative modeling of cellular processes, and cellular engineering. I will also supplement my previous training and experience in teaching and mentorship with new training in advocacy to best position myself to mentor my future trainees and further justice, diversity, equity, and inclusion throughout the scientific enterprise. Through my proposed research and training, I will be well positioned to transition to an independent position where I can achieve my scientific and advocacy goals.

项目概要人类生理学取决于细胞对环境信号的精确反应。响应的特异性环境信号是通过特定的蛋白质组、转录组、表观基因组和非遗传来实现的细胞状态。在生理状态下，健康细胞与其周围组织协调运作，执行对环境刺激作出反应的特定功能。在疾病中，细胞状态失调可以预防细胞产生必要的反应并导致独立于生理环境的增殖。了解细胞状态如何驱动细胞功能对于了解健康和健康中的组织功能至关重要疾病，并且是工程细胞疗法所必需的，能够实现由其靶标编码的特定行为环境。尽管对单细胞生物学进行了数十年的研究，但我们仍然不了解其基本原理将细胞状态与细胞对其环境的反应特异性联系起来的原理在我提出的研究中，我将使用合成生物学工具来定量探讨这种联系细胞状态和信号传导特异性之间的关系。我提出的工作将深入了解细胞如何不同的类型对其环境做出独特的反应，并将生成计算模型可用于设计细胞行为。研究不同类型的细胞如何独特地响应同样的信号，我将使用光遗传学来干扰早期候选细胞类型中的模型信号 cAMP 小鼠胚胎和发育中的斑马鱼的无偏筛选。我对小鼠胚胎干细胞的研究将作为通过细胞内信号传导控制细胞类型和重新连接细胞的原理证明基因表达程序的反应。我在斑马鱼方面的工作将产生一个预测模型，可以仅使用来自该细胞的转录数据来推断给定细胞对刺激的独特反应。在整个工作中，我将专注于生成可解释的计算模型，这些模型可用于未来设计细胞行为。我将通过综合我之前在神经科学、细胞信号传导、和应用合成生物学，建议进行发育生物学、基因组学、定量细胞过程建模和细胞工程。我也会补充之前的训练和教学和指导方面的经验以及新的宣传培训，使自己能够最好地指导我的未来的受训者，并进一步促进整个科学事业的公正、多样性、公平和包容性。通过我提议的研究和培训，我将能够很好地过渡到一个独立的职位，在那里我可以实现我的科学和宣传目标。