Treponema - Host Cell and Tissue Interactions

密螺旋体 - 宿主细胞和组织的相互作用

• 批准号: 10551350
• 负责人: J CHRISTOPHER FENNO
• 金额: $ 59.53万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10551350
• 关键词: Acylation; Affect; Alveolar Bone Loss; Animal Model; Behavior; Binding; Biochemical; Biological Assay; Biology; Calcium; Cell Separation; Cell model; Cells; Chronic; Complex; Cytopathology; Cytoskeleton; Data; Disease; Disease Progression; Environment; Event; Extracellular Matrix; Fibronectins; Gelatinase A; Generations; Genetic; Goals; Health Transition; Homeostasis; Human; Immune response; Individual; Inflammatory; Integration Host Factors; Integrins; Intercellular Junctions; Knowledge; Lesion; Lipoproteins; Maintenance; Matrix Metalloproteinases; Mediating; Mediator; Membrane; Membrane Proteins; Metabolic; Molecular Analysis; Molecular Biology; Mouth Diseases; Mutation; Nisin; Oral; Order Spirochaetales; PTK2 gene; Parents; Pathway interactions; Penetration; Peptide Hydrolases; Periodontal Diseases; Periodontal Ligament; Periodontitis; Phosphorylcholine; Positioning Attribute; Proteins; Qualifying; Recombinant Proteins; Research; Role; Signal Transduction; Surface; TLR2 gene; Testing; Tissues; Tooth Socket; Tooth structure; Treponema; Treponema denticola; VDAC1 gene; alveolar bone; antimicrobial peptide; bacteriocin; chronic infection; cytotoxic; dentilisin; dysbiosis; experience; genetic analysis; genetic manipulation; host-microbe interactions; immunoregulation; in vivo; insight; interest; intermolecular interaction; lipooligosaccharide; model organism; mouse model; mutant; oral spirochetes; osteoblast differentiation; pathobiont; protein complex; protein protein interaction; response; systemic inflammatory response; therapeutic target

ABSTRACT The goal of this research is to characterize the role of Treponema denticola surface proteins in interaction of this human oral spirochete with host tissue, thereby gaining insight into mechanisms by which T. denticola contributes to initiation and progression of periodontal disease. We focus on analysis of T. denticola protein complexes that directly affect cells isolated from tissue comprising the periodontal ligament (PDL) that comprises the junction between the tooth and the alveolar bone of the tooth socket: specifically the PrtP lipoprotein protease complex (dentilisin) and the oligomeric Msp protein. Our overall hypothesis is that dentilisin and Msp are major contributors to T. denticola cytopathic behavior in periodontal disease, In this context we will examine specific domains of dentilisin and Msp, as well as the T. denticola lipooligosaccharide component of the outer membrane. To characterize their specific roles in microbe-host interactions, our approach is to utilize purified native and recombinant proteins as well as isogenic T. denticola strains carrying defined mutations in individual components of these outer membrane complexes. We will first extend our ongoing studies characterizing dentilisin and Msp assembly in the Td outer membrane. Then, to further studies of host responses to challenge by Td and its specific components, we will then characterize in a cell model T. denticola-induced dysregulation of TLR/MyD88 and Integrin/FAK signaling mechanisms and consequences for the cytoskeleton as well as expression and activity of matrix metalloproteinases. We will determine the extent to and the mechanisms by which specific T. denticola components contribute to tissue destruction in a mouse model of periodontal disease. Finally, we will test the ability of the the antimicrobial peptide nisin to modulate T. denticola-induced dysbiotic signaling in both the cell and animal models. Our research team is uniquely positioned to conduct these studies, with combined expertise in spirochete molecular biology, extracellular matrix biology and cytopathology of inflammatory diseases. Completion of this project will contribute to both basic knowledge of spirochete molecular biology and to understanding of microbe-host interactions in chronic infections such as periodontal diseases.

摘要 本研究的目的是表征齿密螺旋体表面蛋白在相互作用中的作用。 这种人类口腔螺旋体与宿主组织，从而获得洞察机制，通过 导致牙周病的发生和发展。我们重点分析齿状毛滴虫蛋白。 直接影响从组成牙周膜(PDL)的组织中分离出来的细胞的复合体 包括牙齿与牙窝的牙槽骨交界处，具体为PRTP 脂蛋白水解酶复合体(牙本质蛋白)和寡聚体MSP蛋白。我们的总体假设是 牙菌素和MSP是齿状毛滴虫在牙周疾病中细胞病变行为的主要贡献者。 背景我们将研究牙本质蛋白和MSP的特定结构域，以及齿状棘球菌脂低聚糖 外膜的组成部分。为了确定它们在微生物-宿主相互作用中的具体作用，我们的 方法是利用纯化的天然和重组蛋白以及携带有 这些外膜复合体的个别成分有明确的突变。我们将首先将我们的 正在进行的研究表征牙菌素和MSP在TD外膜中的组装。然后，为了进一步的研究 然后，我们将在细胞模型T中表征宿主对TD及其特定成分的攻击反应。 齿状幼虫诱导的TLR/MyD88和整合素/FAK信号转导机制及后果 细胞骨架以及基质金属蛋白酶的表达和活性。我们将确定其程度 以及齿状毛滴虫特定成分对小鼠组织的破坏作用及其机制 牙周病模型。最后，我们将测试抗菌肽Nisin对T. 在细胞和动物模型中，丹皮考拉诱导的非生物信号转导。我们的研究团队独一无二 定位于进行这些研究，并结合螺旋体分子生物学、细胞外 炎症性疾病的基质生物学和细胞病理学。该项目的完成将对双方都有所贡献 了解螺旋体分子生物学的基础知识，了解慢性支气管炎患者的微生物-宿主相互作用 感染，如牙周病。