TOWARDS UNDERSTANDING THE NON-CLASSICAL SECRETION OF HUMAN INTERLEUKIN-1 ALPHA

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 白介素s(IL‘s)参与了与感染、炎症和自身免疫相关的多种生物学过程。尤其是IL-1‘S是促炎细胞因子，它们帮助宿主抵抗感染。已知的是，S缺乏IL-1会导致细菌感染致死。此外，最近的研究表明，IL-1还在伤口愈合、癌症发生、肿瘤侵袭、类风湿性关节炎和阿尔茨海默病中发挥作用。IL-1β缺乏N-末端信号肽，因此与大多数其他胞外蛋白不同，它不是通过经典的内质网状高尔基体途径分泌的。初步研究表明，在铜存在的情况下，IL-1通过与钙结合蛋白S100A13形成多蛋白复合体而释放到细胞外。尽管有关于IL-1信号传递过程的有用信息，但IL-1分泌到细胞外间隔的确切机制尚不清楚。到目前为止，由于IL-1在哺乳动物细胞中过表达的困难，其结构功能数据一直有限。在此背景下，本研究旨在全面了解IL-1的非经典释放及其与铜和S100A13的结合。这一建议的具体目的包括：1)测定IL-1与铜和S100A13的结合亲和力；2)表征非经典分泌IL-1所必需的分子相互作用。对IL-1非经典分泌的全面了解将为理解无信号肽的蛋白质输出的一般原理提供有价值的信息。此外，在供资期间，该项目将吸引许多本科生和硕士研究生参与独立研究，加强他们对科学原理的学习，使他们有机会为研究做出独特贡献，并使他们有机会对IL-1在这一毁灭性疾病家族中所起的作用做出独特贡献，并激发他们对未来生物医学研究职业的兴奋。此外，这项申请的资金将扩大学生对蛋白质稳定性、结构和功能的研究，并使更多来自肯塔基州的学生成功进入生物医学研究生课程。肯塔基州传统上在生物医学科学中的代表性较低。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Interleukins (IL's) are involved in a wide spectrum of biological processes associated with infection, inflammation, and autoimmunity. IL-1's in particular are pro-inflammatory cytokines, and they assist the host in fighting infection. Deficiency in IL-1's is known to result in lethality in bacterial infections. In addition, recent studies suggest that IL-1¿ also plays a role in wound healing, carcinogenesis, tumor invasion, rheumatoid arthritis, and Alzheimer's disease. IL-1¿ lacks the N-terminal signal peptide, therefore, unlike most other extracellular proteins, it is not secreted through the classical endoplasmic recticulum  Golgi pathway. Preliminary studies have suggested that the release of IL-1¿ into the extracellular compartment occurs by the formation of a multi-protein complex to the calcium- binding protein, S100A13 in the presence of copper. Although useful information exists on the IL-1 signaling process, the exact mechanism of IL-1¿ secretion into the extracellular compartment is not clear. Until now structure- function data have been limited for IL-1¿ because of the difficulty in its overexpression in mammalian cells. In this context, the purpose of the proposed research is to fully understand IL-1¿'s non-classical release and it's binding to copper and S100A13. Specific aims of this proposal include: 1) determing the binding affinity of IL-1¿ for copper and S100A13; 2) characterizing the molecular interactions necessary for the non-classical secretion of IL-1¿. A complete understanding of the non-classical secretion of IL-1¿ will provide valuable information towards understanding the general principles of export of proteins without signal peptide. Furthermore, over the funding period, this project will engage numerous undergraduates and master's level graduate students in independent research, enhancing their learning of scientific principles, giving them an opportunity to make unique contributions to the study the role played by IL-1¿ in this devastating family of diseases, and stimulating their excitement for future careers in biomedical research. Moreover, the funding of this application will expand student research in protein stability, structure and function and enable more students from Kentucky, a state traditionally underrepresented in biomedical sciences, to successfully advance into biomedical graduate programs.