Resolving functional aggregates: A new perspective on innate immune control

先天免疫系统中的模式识别受体(PRR)形成了抵御病毒的第一道防线 病原体种类繁多。PRRs及其下游的信号分子通常形成聚集态 大分子组装体，并利用这种组装体的免疫学功能。这些 这些发现改变了我们对先天免疫系统如何检测微生物感染和 它是如何激活抗微生物免疫反应的。然而，这些“功能聚合”是怎样的呢？ 解决了它们的组装问题，以确保潜在有害炎症的瞬时激活 信号未知。这些功能聚集体是如何与细胞蛋白质质量控制相互作用的 (PQC)系统，负责分解错误折叠的蛋白质聚集体(例如淀粉样蛋白)？有没有共同点，还是 更确切地说，是细胞对功能错误折叠的聚集体和功能失调的聚集体的反应存在差异？海流 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，很少有相关研究解决这些问题。我们的战略是利用 多学科方法，从系统功能筛选到生化重建，再到结构 解剖。这些方法的结合肯定会产生深刻的机械性理解 先天免疫中的功能聚集体被分解。它还将提供一个新的范例，说明先天的 免疫系统受到调节，以及如何进一步控制它以获得治疗收益。此外， 考虑到新出现的一种观点，即许多蛋白质形成集合体或颗粒作为 正常生理(例如胞浆RNA颗粒和核斑点)，我们的发现和策略有 其影响远远超出了先天免疫系统。 目前的应用代表了我研究的一个新方向。与我们以前和现在的工作不同， 主要集中在微生物感染如何激活先天性免疫反应的机制上， 这项应用重点研究一旦激活，细胞如何关闭免疫信号的机制。在……里面 具体地说，我建议探索先天免疫和细胞之间以前未被认识到的接口。 PQC，寻求管理先天免疫信号复合体和错误折叠的新统一原则 功能失调的集合体。这一应用的基础是我识别小说的一般科学方法 学科之间的联系，推动领域的现有边界。虽然这项提案涉及 具有高风险和挑战性的问题，作为发现功能的先驱实验室之一 对于先天免疫的聚合，我相信我们处于独特的地位，可以打开这一新的研究领域。

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.