Shedding new light on cytokine signaling through molecular engineering

项目摘要/摘要 细胞因子信号转导对于启动针对微生物感染和癌症的免疫反应是必不可少的。 免疫系统由两种防御机制组成，即先天免疫和获得性免疫 这两个系统都严重依赖细胞因子信号来发挥作用。先天免疫系统很早就起作用了 在感染或癌症期间，包括I型干扰素反应。适应性免疫系统变得完全 大约七天后就会活跃起来。尽管这一反应相对于先天系统是延迟的，但时间 是建立强大和特异的T细胞反应所必需的。白介素2和干扰素-γ是 影响适应性免疫系统反应的细胞因子的例子。还有几十个其他的 细胞因子家族在免疫系统中扮演着重要的角色，包括造血、炎症、 细胞凋亡和许多其他的细胞凋亡。了解细胞因子如何发出信号，它们诱导的基因，以及它们的 功能对于了解人类健康和疾病至关重要。基因工程细胞因子的最新实例 证明调节细胞因子信号可以极大地改变细胞因子的反应，并可能提供 新的治疗方法。在这项提案中，我们的目标是使用蛋白质工程技术来填补大型 细胞因子信号转导知识的空白可能揭示新的治疗靶点和方法 干预。 细胞因子信号传递的范式是细胞因子驱动细胞因子受体的二聚化。亚努斯 激酶(JAK)被认为是与细胞因子受体结构性结合的。在受体二聚化后， 雅克雅克会相互交叉磷酸化，也会使受体相互磷酸化。转录信号转导和激活因子 (STATs)与磷酸化的受体结合，然后被磷酸化、二聚化和转位到细胞核 以引起基因和功能反应。我们实验室最新的工具开发提供了一种简化的方法 描述发生在细胞内的蛋白质-蛋白质相互作用，挑战该领域的假设，以及 提供一个机会来了解细胞因子信号传递的每一步是如何对细胞因子信号传递做出贡献的。我们 目的展示改变这些相互作用如何调节细胞因子、信号和反应基因以及功能标志。

Project Summary/Abstract Cytokine signaling is essential to the initiation of the immune response against microbial infection and cancer. The immune system is composed of two mechanisms of defense defined as the innate and adaptive immune systems, both of which critically rely on cytokine signaling to function. The innate immune system acts early during an infection or cancer and includes the type I IFN response. The adaptive immune system becomes fully active after approximately seven days. Although this response is delayed relative to the innate system, the time is needed to mount a T-cell response that is potent and specific. Interleukin-2 and interferon gamma are examples of cytokines that shape the response of the adaptive immune system. There are dozens of other cytokine families that each play an important role in the immune system including hematopoiesis, inflammation, apoptosis as well as many others. Understanding how cytokines signal, the genes they induce, and their functions are critical to understanding human health and disease. Recent examples of engineered cytokines demonstrate that tuning of cytokine signaling can drastically alter a cytokine’s response and may offer promising new therapeutic approaches. In this proposal, we aim to use protein engineering technologies to fill the large gaps in knowledge of cytokine signaling which may reveal new targets and approaches for therapeutic intervention. The paradigm of cytokine signaling is that cytokines drive the dimerization of cytokine receptors. Janus kinases (JAKs) are believed to be constitutively bound to the cytokine receptors. Upon receptor dimerization, the JAKs cross phosphorylate each other as well as the receptors. Signal transducers and activators of transcription (STATs) bind to the phosphorylated receptors, are then phosphorylated, dimerize, and translocate to the nucleus to elicit gene and functional responses. Recent tool development in our lab provides a streamlined approach to characterize protein-protein interactions which occur intracellularly, challenge assumptions in the field, and provide an opportunity to understand how every step in cytokine signaling contributes to cytokine signaling. We aim to show how altering these interactions tune cytokine signaling and response gene and functional signature.