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.

抽象的 这项研究的目的是表征treponema denticola表面蛋白在相互作用中的作用 这种人类口腔螺旋体带有宿主组织，从而深入了解牙霉菌的机制 有助于牙周疾病的开始和进展。我们专注于分析牙霉菌蛋白 直接影响从包含牙周韧带（PDL）的组织分离的细胞的复合物 包括牙齿的牙齿和牙槽骨之间的连接：特别是PRTP 脂蛋白蛋白酶复合物（棘硅蛋白酶）和寡聚MSP蛋白。我们的总体假设是 牙齿和MSP是牙周疾病中牙霉细胞性行为的主要因素，在此中 上下文我们将检查牙脂和MSP的特定域，以及T. denticola脂肪含糖。 外膜的组成部分。为了表征其在微生物 - 宿主相互作用中的特定角色，我们 方法是利用纯化的天然和重组蛋白以及携带的牙本质T. denticola菌株 这些外膜复合物的各个组件中定义的突变。我们将首先扩展我们的 正在进行的研究表征了TD外膜中牙脂素和MSP组件的曲目。然后，进一步研究 TD及其特定组件对挑战的主机响应，我们将在细胞模型T中进行表征。 TLR/MYD88和整合素/FAK信号传导机制和后果的牙齿诱导的失调 基质金属蛋白酶的细胞骨架以及表达和活性。我们将确定程度 对特定牙霉菌成分有助于小鼠组织破坏的特异性和机制 牙周疾病的模型。最后，我们将测试抗微生物肽尼生蛋白调节T的能力。 牙齿诱导的细胞和动物模型中诱导的失调信号传导。我们的研究团队是独特的 定位于进行这些研究，并具有螺旋体分子生物学的联合专业知识，细胞外 炎症性疾病的基质生物学和细胞病理学。该项目的完成将有助于两者 螺旋体分子生物学的基本知识以及了解慢性的微生物 - 宿主相互作用 感染，例如牙周疾病。