Membrane Protein Effectors of Pathogen Interactions With Host

病原体与宿主相互作用的膜蛋白效应子

• 批准号: 10404547
• 负责人: Francesca M Marassi
• 金额: $ 25.45万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10404547
• 关键词: Address; Age related macular degeneration; Alzheimer' s Disease; Bacterial Outer Membrane Proteins; Blood Proteins; Cell Adhesion; Cell surface; Complement; Deposition; Diagnostic; Disease; Environment; Goals; Health; Hemostatic function; Host Defense; Human; Immunity; Knowledge; Lipids; Medical Research; Membrane Proteins; Natural Immunity; Pathogenesis; Pathologic; Play; Preventive; Process; Proteins; Research; Research Project Grants; Role; Structure; Techniques; Therapeutic; Yersinia pestis; age related; cell motility; design; drug development; knowledge base; microbial; multidisciplinary; pathogen; pathogenic bacteria; pathogenic microbe; public health relevance; recruit; solid state nuclear magnetic resonance; stressor; structural biology; targeted treatment

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

摘要 病原菌与寄主相互作用的膜蛋白效应因子。这个项目的目标是开发一种 了解人类宿主防御与微生物病原体和 年龄相关的压力源。许多病原体已经进化出一种策略，通过招募 补充微生物细胞表面的调节因子。此外，在年代中形成的异位沉积- 相关性黄斑变性(AMD)和阿尔茨海默病(AD)也富含血液蛋白质，参与 先天免疫力。尽管这些过程在生物医学上很重要，但机械知识是有限的。这 研究项目就是为了解决这一知识差距而设计的。我们的重点是确定 人血蛋白参与免疫的两种中枢相互作用：止血、细胞黏附和细胞 迁移：(1)与来自细菌病原体鼠疫耶尔森氏菌的外膜蛋白相互作用 重要的致病机制，以及(2)与脂质和生物矿物质的相互作用，这与 与AMD和AD相关的病理性沉积。在这些高度异质的环境中，蛋白质扮演着 在人类健康中的核心作用，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 这一根本的知识鸿沟。解决这些问题，对于全面推进 了解疾病的过程，并开发诊断、预防和治疗方法。这个 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，特别是溶液 核磁共振和固体核磁共振。 1