Phenotype Engineering by Signaling Network Modification

细胞受到外部信号的轰击，并根据其内部信号网络的动态作出反应。物种、个体甚至组织类型之间的遗传变异可能导致对相同外部信号的不同反应：人类和小鼠对药物治疗的反应可能不同，某些癌细胞对化疗药物表现出耐药性，而另一些则是敏感的。通过使用实验和理论技术操纵潜在的信号网络，该项目解决了来自不同物种或个体的细胞如何以不同的方式对相同的外部化学信号作出反应的问题。通过证明细胞内部信号网络的定向扰动可以导致特定的生理变化，这项研究将通过提出改善治疗干预措施的功效和增强人类疾病的动物模型来改进医学研究。尽管遗传变异在解释不同细胞类型的不同反应方面很重要，但人们对哪种遗传改变负责知之甚少。为了解决这一知识差距，本项目利用计算建模和有针对性的实验，在线虫属的一个特征良好的信号网络。这项工作的重点是EGF、Wnt和Notch信号之间的关系，这些信号通路在人类发育和癌症等疾病中都很重要。该项目的目标是确定细胞内部信号网络的定向扰动，从而导致特定的生理变化。该项目将确定一种合理的方法来评估网络和有意地设计扰动，以改进人类疾病的动物模型，并扩大效用或以其他方式提高治疗剂的功效。该项目还支持数学和生物学跨学科应用方面的培训，重点是本科生和来自代表性不足群体的学生。

Cells are bombarded with external signals, and respond based on the dynamics of their internal signaling networks. Genetic variability between species, individuals, and even tissue types can result in divergent responses to the same external signal: humans and mice may respond differently to a drug treatment, and certain cancer cells exhibit resistance to a chemotherapeutic agent while others are sensitive. By manipulating the underlying signalling networks using experimental and theoretical techniques, this project addresses the question of how cells from different species or individuals may respond in a dissimilar manner to the same external chemical signal. By demonstrating that directed perturbations of a cell's internal signaling network can lead to specific physiological changes, this research will improve medical research by suggesting improvements to the efficacy of therapeutic interventions and enhancements to animal models of human diseases.Despite the importance of genetic variability in explaining disparate responses in varied cell types, very little is known about which genetic alterations are responsible. To address this knowledge gap, this project utilizes computational modeling and targeted experimentation on a well-characterized signaling network in nematodes of the Caenorhabditis genus. The work focuses on the relationship between the EGF, Wnt and Notch signaling, pathways that are known to be important in human development and diseases such as cancer. The project goal is to identify the directed perturbations of a cell's internal signaling network that can lead to specific physiological changes. The project will define a rational approach to evaluating networks and intentionally engineering perturbations to improve animal models of human disease, and to broaden the utility or otherwise enhance the efficacy of therapeutic agents. The project also supports training in interdisciplinary applications of mathematics and biology, with an emphasis on undergraduate students and students from underrepresented groups.