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

理解人类 IL-1 ALPHA 的非经典分泌

• 批准号: 8168302
• 负责人: Rajalingam Dakshinamurthy
• 金额: $ 3.36万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8168302
• 关键词: Affinity; Alzheimer' s Disease; Autoimmunity; Bacterial Infections; Binding; Biological Process; Biomedical Research; Calcium-Binding Proteins; Computer Retrieval of Information on Scientific Projects Database; Copper; Data; Disease; Extracellular Protein; Family; Funding; Future; Golgi Apparatus; Grant; Human; Infection; Inflammation; Inflammatory; Institution; Interleukin-1; Interleukin-1 alpha; Interleukins; Kentucky; Learning; Mammalian Cell; N-terminal; Pathway interactions; Peptide Signal Sequences; Play; Protein Export Pathway; Proteins; Research; Research Personnel; Resources; Rheumatoid Arthritis; Role; Science; Source; Structure; Students; Tumor Cell Invasion; United States National Institutes of Health; Wound Healing; carcinogenesis; career; computerized data processing; cytokine; extracellular; fighting; graduate student; overexpression; programs; protein complex

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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以出现在其他 CRISP 条目中 列出的机构是。 中心，不一定是研究者的机构。 白细胞介素 (IL's) 参与与感染、炎症和自身免疫相关的多种生物过程，尤其是 IL-1 是促炎性细胞因子，已知它们可以帮助宿主对抗感染。此外，最近的研究表明 IL-1¿还在伤口愈合、癌变、肿瘤侵袭、类风湿性关节炎和阿尔茨海默氏病中发挥作用。缺乏 N 末端信号肽，因此，与大多数其他细胞外蛋白不同，它不是通过经典的内质网高尔基体途径分泌的。初步研究表明 IL-1 的释放。尽管存在有关 IL-1 信号传导过程的有用信息，但 IL-1 的确切机制是通过与钙结合蛋白 S100A13 形成多蛋白复合物而进入细胞外区室的。迄今为止，IL-1 的结构功能数据仍有限。由于其在哺乳动物细胞中过度表达的困难，因此本研究的目的是充分了解 IL-1¿该提案的非经典释放及其与铜和 S100A13 的结合包括：1) 确定 IL-1 的结合亲和力。对于铜和 S100A13；2) 表征 IL-1 非经典分泌所需的分子相互作用.对IL-1非经典分泌的完整理解¿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，在资助期间，该项目将吸引众多本科生和硕士研究生进行独立研究，增强他们对科学原理的学习，为他们提供机会。为研究 IL-1 所发挥的作用做出独特贡献¿此外，该申请的资助将扩大学生在蛋白质稳定性、结构和功能方面的研究，并使更多来自肯塔基州的学生能够参与其中，而肯塔基州传统上在生物医学领域的代表性不足。 ，成功升入生物医学研究生课程。