Resolving functional aggregates: A new perspective on innate immune control

解决功能聚集：先天免疫控制的新视角

基本信息

批准号：
10217977
负责人：
Sun Hur
金额：
$ 123.9万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-30 至 2024-07-31
项目状态：
已结题

项目摘要

Pattern Recognition Receptors (PRRs) in the innate immune system form the first line of defense against a broad range of pathogens. PRRs and their downstream signaling molecules often form aggregate-like macromolecular assemblies and that they utilize such assemblies for their immunological functions. These findings have transformed our understanding of how the innate immune system detects microbial infection and how it activates the anti-microbial immune response. However, how these “functional aggregates” are resolved upon their assembly to ensure transient activation of the potentially harmful inflammatory signal is not known. How do these functional aggregates interact with the cellular protein quality control (PQC) system, charged with resolving misfolded protein aggregates (e.g. amyloids)? Is there a commonality or rather a divergence in cellular response to functional vs. dysfunctional misfolded aggregates? The current application aims to address these questions by exploring the connections between innate immunity and PQC. This is uncharted territory, with only few relevant studies that address such questions. Our strategy is to utilize multidisciplinary approaches, from systematic functional screens to biochemical reconstitution and to structural dissection. The combination of these approaches is sure to generate deep mechanistic understanding of how functional aggregates in innate immunity are resolved. It will also provide a new paradigm for how the innate immune system is regulated and how it can be further controlled for therapeutic gains. Furthermore, considering the emerging view that many proteins form aggregates-like assemblies or granules as part of normal physiology (e.g. cytosolic RNA granules and nuclear speckles), our findings and strategies have implications far beyond the innate immune system. The current application represents a new direction in my research. Unlike our previous and current work, which has largely focused on the mechanisms of how microbial infection activates innate immune response, this application focuses on the mechanisms of how cells turn off the immune signaling once activated. In particular, I propose to explore the previously unappreciated interface between innate immunity and cellular PQC, seeking new unifying principles governing both innate immune signaling complexes and misfolded dysfunctional aggregates. Underlying this application is my general scientific approach of identifying novel connections between disciplines and pushing the existing boundaries of the fields. While this proposal deals with highly risky and challenging problems, as one of the pioneering laboratories for the discovery of functional aggregates in innate immunity, I believe that we are uniquely positioned to open this new area of research.

先天免疫系统中的模式识别受体 (PRR) 构成了针对病毒的第一道防线。广泛的病原体及其下游信号分子通常形成聚集体状。大分子组装体以及它们利用此类组装体来实现其免疫功能。研究结果改变了我们对先天免疫系统如何检测微生物感染和然而，这些“功能性聚集体”是如何激活的。解决了它们的组装，以确保潜在有害的炎症的短暂激活信号如何与细胞蛋白质质量控制相互作用尚不清楚。（PQC）系统，负责解决错误折叠的蛋白质聚集体（例如淀粉样蛋白）？相反，细胞对功能性错误折叠聚集体和功能失调性错误折叠聚集体的反应存在差异？该应用程序旨在通过探索先天免疫和 PQC 之间的联系来解决这些问题。这是一个未知的领域，只有很少的相关研究来解决这些问题，我们的策略是利用。多学科方法，从系统功能筛选到生化重建和结构这些方法的结合肯定会产生对如何进行深入的机械理解。先天免疫中的功能聚集体的解决也将为先天免疫的如何解决提供一个新的范例。免疫系统受到调节以及如何进一步控制免疫系统以获得治疗效果。考虑到许多蛋白质形成聚集体或颗粒作为其一部分的新兴观点正常生理学（例如胞质 RNA 颗粒和核斑点），我们的发现和策略其影响远远超出了先天免疫系统的范围。当前的应用代表了我研究的一个新方向，与我们之前和当前的工作不同。主要关注微生物感染如何激活先天免疫反应的机制，该应用重点关注细胞如何在激活后关闭免疫信号的机制。特别是，我建议探索先天免疫和细胞之间以前未被重视的界面 PQC，寻求新的统一原则来管理先天免疫信号复合物和错误折叠这个应用程序的基础是我识别新奇聚合体的一般科学方法。虽然该提案涉及学科之间的联系并突破现有领域的界限。作为发现功能性物质的先驱实验室之一，面临着高风险和挑战性的问题聚集在先天免疫中，我相信我们处于独特的地位来开辟这个新的研究领域。