Membrane Protein Effectors of Pathogen Interactions With Host

摘要 病原体与宿主相互作用的膜蛋白效应器。该项目的目标是开发一个 了解人类宿主防御与微生物病原体相互作用的方式的框架 与年龄相关的压力源。许多病原体已经进化出通过招募来逃避先天免疫的策略 将调节因子补充到微生物细胞表面。此外，年龄形成的异位沉积物 相关的黄斑变性（AMD）和阿尔茨海默氏病（AD）也富含参与 先天免疫。尽管这些过程具有生物医学重要性，但机械知识仍然有限。这个 研究项目旨在解决这一知识差距。我们专注于确定结构基础 人体血液蛋白的两个主要相互作用涉及免疫、止血和细胞粘附以及细胞 迁移：（1）与细菌病原体鼠疫耶尔森氏菌的外膜蛋白相互作用 对于发病机制很重要，以及（2）与脂质和生物矿物质的相互作用，这些相互作用与形成相关 与 AMD 和 AD 相关的病理沉积。蛋白质在这些高度异质的环境中发挥作用 在人类健康中发挥着核心作用，但在科学知识库中的代表性严重不足。我们的目标是架起桥梁 这一基本知识差距。解决好这些问题对于推进综合治理具有重要意义。 了解疾病过程以及制定诊断、预防和治疗方法。的 研究策略是多学科的。它在很大程度上依赖于结构生物学技术，特别是解决方案 核磁共振和固态核磁共振。 1

SUMMARY Membrane protein effectors of pathogen interactions with host. The goal of this project is to develop a framework for understanding the way in which the human host defenses interact with microbial pathogens and age-related stressors. Many pathogens have evolved strategies to evade innate immunity by recruiting complement regulatory factors onto the microbial cell surface. Moreover, the ectopic deposits that form in age- related macular degeneration (AMD) and Alzheimer's disease (AD) are also rich in blood proteins involved in innate immunity. Despite the biomedical importance of these processes, mechanistic knowledge is limited. This research project is designed to address this knowledge gap. We focus on determining the structural basis for two central interactions of human blood proteins involved in immunity, hemostasis and cell adhesion and cell migration: (1) interactions with outer membrane proteins from the bacterial pathogen Yersinia pestis that are important for pathogenesis, and (2) interactions with lipids and biominerals that are relevant to the formation of pathological deposits associated with AMD and AD. Proteins in these highly heterogenous environments play central roles in human health but are highly under-represented in the scientific knowledge base. We aim to bridge this fundamental knowledge gap. Addressing these problems is important for advancing comprehensive knowledge of the disease process and for developing diagnostic, preventive, and therapeutic approaches. The research strategy is multidisciplinary. It relies significantly on structural biology techniques, particularly solution NMR and solid-state NMR. 1