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

• 批准号: 10456170
• 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
• 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
• 来源: https://reporter.nih.gov/project-details/10456170
• 关键词: Address; Amyloid; Area; Biochemical; Cells; Charge; Complex; Cytoplasmic Granules; Discipline; Disease; Dissection; Ensure; Goals; Immune; Immune response; Immune signaling; Infection; Inflammatory; Innate Immune Response; Innate Immune System; Laboratories; Molecular; Natural Immunity; Nuclear; Pattern recognition receptor; Physiology; Positioning Attribute; Proteins; Quality Control; RNA; Research; Signal Transduction; Signaling Molecule; System; Therapeutic; Work; antimicrobial; immune function; innate immune function; innate immune mechanisms; interdisciplinary approach; macromolecular assembly; microbial; misfolded protein; novel; pathogen; protein aggregation; reconstitution; response

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）形成了抵抗免疫缺陷的第一道防线。 广泛的病原体。PRR及其下游信号分子通常形成聚集体样 大分子组装体，并且它们利用这样的组装体用于它们的免疫功能。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的理解， 它是如何激活抗微生物免疫反应的然而，这些“功能性聚集体”是如何 在它们组装时决定，以确保瞬时激活潜在有害的炎性细胞， 信号是未知的。这些功能性聚集体如何与细胞蛋白质质量控制相互作用 (PQC)系统，负责解析错误折叠的蛋白质聚集体（例如淀粉样蛋白）？有没有共同点或者 而是细胞对功能性与功能失调性错误折叠聚集体的反应的分歧？当前 本申请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涉及这些问题。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 解剖这些方法的结合肯定会产生深刻的机械理解， 先天免疫中的功能聚集体被解决。它也将提供一个新的范例， 免疫系统的调节以及如何进一步控制免疫系统以获得治疗效果。此外，委员会认为， 考虑到新兴的观点，许多蛋白质形成聚集体样的组件或颗粒的一部分， 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。 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， 其主要集中在微生物感染如何激活先天免疫应答的机制上， 本申请集中于细胞一旦被激活如何关闭免疫信号传导的机制。在 特别是，我建议探索先天免疫和细胞免疫之间以前未被重视的接口， PQC，寻求新的统一原则，管理先天免疫信号复合物和错误折叠 功能失调的聚集体。这个应用程序的基础是我的一般科学方法， 学科之间的联系，并推动现有领域的边界。虽然这项提案涉及 高风险和具有挑战性的问题，作为一个开拓性的实验室，为发现功能 我相信，我们处于独特的地位，可以打开这一新的研究领域。