Understanding and rewiring cellular behavior with synthetic biology approaches

项目总结 人类生理依赖于细胞对环境信号的精确反应。答复中的特定性 环境信号是通过特定的蛋白质组、转录组、表观基因组和非基因实现的 细胞状态。在生理状态下，健康的细胞与其周围的组织和谐运作， 对环境刺激作出反应的特定功能。在疾病中，细胞状态的失调可以防止 阻止细胞产生必要的反应，并导致不依赖于生理环境的增殖。 了解细胞状态是如何驱动细胞功能的，对于了解健康和 疾病，是设计细胞疗法所必需的，这些细胞疗法能够根据目标编码的特定行为 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 将细胞状态与细胞对环境的反应的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地探索两者之间的联系 细胞状态和信号特异性之间的关系。我提议的工作将提供对细胞如何 不同的类型实现对其环境的独特响应，并将生成计算模型 可以用来设计细胞行为。为了研究不同类型的细胞如何对 同样的信号，我将使用光遗传学来扰动候选细胞类型的早期模型信号cAMP 在小鼠胚胎和在一个公正的屏幕上发育斑马鱼。我对小鼠胚胎干细胞的研究 将作为通过细胞内信号控制细胞类型和重新连接细胞的原则证明 用基因表达程序进行反应。我在斑马鱼方面的工作将产生一种预测模型，它可以 被用来推断给定细胞对刺激的独特反应，仅使用该细胞的转录数据。 在这项工作中，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。 我将通过综合我以前在神经科学、细胞信号转导、 和应用合成生物学，并建议培训在发育生物学，基因组学，定量 细胞过程建模和细胞工程。我还将补充我之前的训练和 在教学和指导方面的经验，以及新的宣传培训，使我能够最好地指导我的 未来的受训者以及整个科学事业的进一步公正、多样性、公平和包容性。穿过 我提议的研究和培训，我将处于有利地位，过渡到一个独立的职位，在那里我 可以实现我的科学和倡导目标。

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.