Bioinorganic Explorations of Host-Defense Proteins

宿主防御蛋白的生物无机探索

• 批准号: 9239551
• 负责人: ELIZABETH M NOLAN
• 金额: $ 26.96万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9239551
• 关键词: Affinity; Animal Model; Antibiotics; Binding; Bioavailable; Biochemical; Biological; Biological Assay; Biological Process; Biophysics; C-terminal; Calcium; Cations; Chelating Agents; Chemistry; Communicable Diseases; Crystallization; Data; Development; Dimerization; Disease; Divalent Cations; EF Hand Motifs; EF-Hand Domain; Electron Spin Resonance Spectroscopy; Epithelial Cells; Exhibits; Extracellular Space; Growth; Health; Homeostasis; Host Defense; Human; Human Pathology; Immune response; Infection; Inflammation; Innate Immune Response; Innate Immune System; Intercept; Invaded; Investigation; Ions; Iron; Knowledge; Leukocyte L1 Antigen Complex; Literature; Malignant Neoplasms; Manganese; Medical; Metals; Methods; Microbe; Modeling; Molecular; Morbidity - disease rate; Mus; NMR Spectroscopy; Natural Immunity; Nutrient; Organism; Outcome; Pathogenesis; Physiological; Play; Process; Property; Proteins; Public Health; Research Proposals; Role; Rosaniline Dyes; S100 Proteins; S100A8 gene; S100A9 gene; Sepsis; Site; Spin Labels; Staphylococcus aureus; Streptococcus pneumoniae; Structure; Tail; Testing; Transition Elements; United States; Work; Zinc; antimicrobial; base; chelation; dimer; extracellular; foodborne; host-microbe interactions; innovation; insight; member; metal chelator; microbial; neutrophil; novel strategies; pathogen; prevent; response; solute; therapeutic development; therapeutic target

PROJECT SUMMARY Transition metal ions are essential nutrients for all organisms. The availability of these nutrients plays a critical role in the host-microbe interaction and microbial pathogenesis. The primary objective of this research proposal is to elucidate how the host-defense protein calprotectin (CP) sequesters transition metals from microbes and thereby contributes to the innate immune response. CP provides a remarkable example of unique biological coordination chemistry that is relevant to infectious disease and microbial pathogenesis. Each CP heterodimer (S100A8/S100A9) exhibits six different sites for chelating divalent cations, including calcium (Ca) and transition metals. Our central hypothesis is that CP responds to physiological Ca(II) gradients to tune its coordination chemistry for transition metals and to modulate its biological function as an antimicrobial protein that deprives invading pathogens of essential nutrient metals (e.g. manganese, iron, zinc). The proposed investigations are based on preliminary data that Ca(II) binding by human CP (hCP) at the EF- hand domains triggers high-affinity chelation of transition metals at sites formed at the interface of the S100A8 and S100A9 subunits. In Aim 1, we will investigate how Ca(II) ions modulate hCP structure and tune its affinities for transition metals. In Aim 2, we will evaluate how the murine orthologue (mCP) sequesters transition metals and thereby provide needed molecular and biophysical insights into literature results of CP from animal models of infection. In Aim 3, we will investigate the competition between CP and bacterial metal- transport machinery for manganese(II). These fundamental bioinorganic and biophysical initiatives constitute an innovative departure from biological and medical studies of CP, and highlight the importance of applying quantitative analytical and spectroscopic methods to a problem central to human health and disease. Taken together, the results will provide new molecular insights into how CP contributes to innate immunity and metal homeostasis. Moreover, the ability to acquire metal ions is an important facet of microbial pathogenesis, and both intercepting microbial metal acquisition and boosting the metal-withholding response of the host present opportunities for antibiotic development. We anticipate that the results from our work will, in the long term, help to guide the development of new antimicrobial therapeutics that target these processes central to the host- pathogen interaction.

项目摘要 过渡金属离子是所有生物的必需营养素。这些营养素的可用性起着至关重要的作用 在宿主微生物相互作用和微生物发病机理中的作用。这项研究的主要目标 提案是为了阐明宿主防御蛋白钙卫蛋白（CP）如何从 微生物，从而有助于先天免疫反应。 CP提供了一个非凡的例子 与传染病和微生物发病机理有关的独特生物协调化学。 每个CP异二聚二聚体（S100A8/S100A9）都有六个不同的地点，用于螯合二价阳离子，包括 钙（CA）和过渡金属。我们的中心假设是CP对生理CA（II）做出反应 调整其用于过渡金属的配位化学的梯度，并将其生物学功能调节为 剥夺了必需养分金属的病原体（例如锰，铁，锌）的抗菌蛋白。 拟议的研究基于初步数据，即人类CP（HCP）在EF-上结合了CA（II） 手部域触发在S100A8界面形成的地点的过渡金属的高亲和力螯合 和S100A9亚基。在AIM 1中，我们将研究Ca（ii）离子如何调节HCP结构并调整其 过渡金属的亲和力。在AIM 2中，我们将评估鼠直系同源物（MCP）隔离器如何 过渡金属，从而为CP的文献结果提供所需的分子和生物物理见解 来自感染动物模型。在AIM 3中，我们将研究CP和细菌金属之间的竞争 锰的运输机械（II）。这些基本的生物有机和生物物理倡议构成 与CP的生物学和医学研究的创新性，并强调了应用的重要性 定量分析方法和光谱方法是人类健康和疾病中心的问题。拍摄 共同的结果将为CP如何促进先天免疫和金属提供新的分子见解 稳态。此外，获得金属离子的能力是微生物发病机理的重要方面，并且 两者都拦截微生物金属采集和提高存在的宿主的金属持有响应 抗生素开发的机会。我们预计我们工作的结果将长期帮助 指导开发新的抗菌治疗剂，这些抗菌疗法针对这些过程的核心核心 - 病原体相互作用。