D3SC: Signaling Axes Modulated by Cyclic Dinucleotides

有了这个奖项，生命过程的化学计划是支持教授赫尔曼O。来自西拉斐特普渡大学的Sintim和Uma Aryal，以确定病毒和细菌的各种分子成分如何激活免疫细胞引起炎症的细节。免疫细胞在消除肿瘤和保护生物体免受病原菌和病毒入侵方面发挥着重要作用。最近在免疫细胞中发现了一种新的通路或信号传导，这种通路或信号传导感测称为环状二核苷酸的分子以控制炎症反应。该项目使用化学探针和蛋白质组学来发现结合环状二核苷酸的蛋白质，以调节免疫细胞中的信号传导。此外，这项研究通过培训研究生和高级本科生来提高STEM的劳动力能力，以获得化学合成，质谱，免疫学和分子生物学方法方面的各种专业技能。已知环状二核苷酸，如环状二鸟苷一磷酸、环状二腺苷一磷酸和环状鸟苷一磷酸-腺苷一磷酸，通过干扰素基因（STING）控制的先天免疫途径的刺激物发出信号，并在多种人类疾病中发挥主要作用，包括各种癌症、病毒和细菌感染以及自身免疫性疾病。到目前为止，环状二核苷酸-STING-TBK 1轴得到了很好的表征，但环状二核苷酸也影响的其他途径和/或蛋白质靶标的表征很差。了解环状二核苷酸如何调节宿主细胞的生理学可以为塑造宿主-病原体相互作用的关键决定因素提供有价值的见解。主要研究人员使用各种STING轴敲除细胞系和蛋白质组学来揭示通过STING和非STING途径的环状二核苷酸介导的途径。他们还在环二核苷酸信号存在下对蛋白质的翻译后修饰进行全局分析。使用新型化学探针，研究人员发现了与环状二核苷酸结合或与STING相关的哺乳动物蛋白质。这项研究提供了深入了解如何环二核苷酸影响哺乳动物细胞中的信号通路超出了良好的表征STING-TBK 1轴。这个奖项反映了NSF的法定使命，并已被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。

With this award, the Chemistry of Life Processes program is supporting the research of Professors Herman O. Sintim and Uma Aryal, from Purdue University, West Lafayette, to determine the details of how various molecular components of viruses and bacteria activate immune cells to cause inflammation. Immune cells play important roles in eliminating tumors and also protecting organisms against invading pathogenic bacteria and viruses. A new pathway or signaling was recently discovered in immune cells, which sense molecules called cyclic dinucleotides to control inflammation response. This project uses chemical probes and proteomics to discover proteins that bind cyclic dinucleotides in order to regulate signaling in immune cells. In addition, this research increases workforce capacity in STEM by training graduate students and advanced undergraduates to acquire a diverse set of specialized skills in chemical synthesis, mass spectrometry, immunology and molecular biology methods. Cyclic dinucleotides, such as cyclic di-guanosine monophosphate, cyclic di-adenosine monophosphate and cyclic guanosine monophosphate–adenosine monophosphate, are known to signal via a stimulator of interferon genes (STING)-controlled innate immune pathway and play major roles in a wide variety of human diseases including various cancers, viral and bacterial infections as well as autoimmune diseases. Thus far, the cyclic dinucleotide-STING-TBK1 axis is well characterized, but other pathways and/or protein targets that cyclic dinucleotides also affect are poorly characterized. Understanding how cyclic dinucleotides regulate host cells physiology could provide valuable insights into key determinants that shape the host-pathogen interaction. The principal investigators use various STING-axis knockout cell lines and proteomics to uncover cyclic dinucleotide mediated pathways that channel through STING and non-STING pathways. They also globally profile post-translational modifications of proteins in the presence of cyclic dinucleotide signals. Using novel chemical probes, the investigators uncover mammalian proteins that bind to cyclic dinucleotides or associate with STING. This study provides insights into how cyclic dinucleotides affect signaling pathways in mammalian cells beyond the well-characterized STING-TBK1 axis.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.