D3SC: Signaling Axes Modulated by Cyclic Dinucleotides

通过这一奖项，生命过程化学项目支持西拉斐特普渡大学的赫尔曼·O·辛蒂姆和乌玛·阿亚尔教授的研究，以确定病毒和细菌的各种分子成分如何激活免疫细胞导致炎症的细节。免疫细胞在清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途径或信号，它可以感应被称为环二核苷酸的分子来控制炎症反应。该项目使用化学探针和蛋白质组学来发现与环二核苷酸结合的蛋白质，以便调节免疫细胞中的信号。此外，这项研究通过培训研究生和高级本科生获得化学合成、质谱学、免疫学和分子生物学方法方面的各种专业技能，增加了STEM的劳动力能力。环二核苷酸，如环二鸟苷一磷酸、环二腺苷一磷酸和环鸟苷一磷酸-腺一磷酸，被认为是通过干扰素基因刺激物(STIN)控制的天然免疫途径来传递信号，并在多种人类疾病中发挥重要作用，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，环二核苷酸-STING-TBK1轴的特征很好，但环二核苷酸也影响的其他途径和/或蛋白质靶点的特征很差。了解环二核苷酸是如何调节宿主细胞生理的，可以为影响宿主与病原体相互作用的关键决定因素提供有价值的见解。主要研究人员使用不同的刺轴敲除细胞系和蛋白质组学来揭示环二核苷酸介导的通路，这些通路通过刺通路和非刺通路进行传递。他们还在全球范围内描述了在存在环二核苷酸信号的情况下蛋白质的翻译后修饰。使用新的化学探针，研究人员发现了与环二核苷酸结合或与刺痛相关的哺乳动物蛋白质。这项研究提供了关于环二核苷酸如何影响哺乳动物细胞中除STING-TBK1轴之外的信号通路的见解。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.