Shedding new light on cytokine signaling through molecular engineering

通过分子工程揭示细胞因子信号传导的新途径

• 批准号: 10501747
• 负责人: Juan Luis Mendoza
• 金额: $ 38.5万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10501747
• 关键词: Adaptive Immune System; Apoptosis; Area; Binding; Biochemistry; Biophysics; Cell Nucleus; Clinical; Cytokine Receptors; Cytokine Signaling; Defense Mechanisms; Dimerization; Disease; Engineering; Family; Genes; Health; Hematopoiesis; Human; Immune response; Immune system; Infection; Inflammation; Innate Immune System; Interferon Type II; Interferons; Interleukin-2; Janus kinase; Knowledge; Light; Malignant Neoplasms; Molecular; Play; Protein Engineering; Proteins; Role; STAT protein; Shapes; Signal Transduction; System; T cell response; Technology; Therapeutic; Therapeutic Intervention; Time; adaptive immune response; cytokine; dimer; immune function; microbial; novel therapeutic intervention; protein protein interaction; receptor; response; tool development

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.

项目摘要/摘要 细胞因子信号传导对于针对微生物感染和癌症的免疫响应的主动性至关重要。 免疫系统由两种定义为先天和适应性免疫的防御机制组成 系统，两者都非常依赖细胞因子信号来发挥作用。先天免疫系统早日起作用 在感染或癌症期间，包括I型IFN反应。自适应免疫系统完全 大约七天后活跃。尽管此响应相对于先天系统延迟了，但时间 需要安装潜在和特定的T细胞响应。白介素-2和干扰素伽玛是 塑造自适应免疫系统反应的细胞因子的例子。还有数十个 细胞因子家族在包括造血，炎症，炎症，包括造血系统中起重要作用的细胞因子家族 凋亡以及许多其他。了解细胞因子如何信号，其影响的基因及其 功能对于理解人类健康和疾病至关重要。工程细胞因子的最新例子 证明细胞因子信号的调整可以大大改变细胞因子的反应，并可能提供承诺 新的治疗方法。在此提案中，我们旨在使用蛋白质工程技术来填充大型 细胞因子信号的知识差距，可能揭示了新的靶标和方法 干涉。 细胞因子信号传导的范式是细胞因子驱动细胞因子接收器的二聚化。贾努斯 激酶（JAKS）被认为是与细胞因子受体结合的。受体二聚体， jaks互相交叉磷酸化以及接收器。转录的信号换能器和激活因子 （统计）与磷酸化受体结合，然后被磷酸化，二聚体并转移到细胞核上 引起基因和功能反应。我们实验室中最近的工具开发提供了一种简化的方法 表征细胞内发生的蛋白质 - 蛋白质相互作用，现场挑战假设，并且 提供一个机会来了解细胞因子信号的每个步骤如何促进细胞因子信号传导。我们 旨在展示改变这些相互作用的方式调整细胞因子信号传导和反应基因以及功能特征。