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 本研究的目的是表征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的关系，从而深入了解齿形毛虫的机制 有助于牙周病的发生和发展。我们专注于 T. denticola 蛋白的分析 直接影响从牙周膜（PDL）组织中分离出来的细胞的复合物 包括牙齿和牙槽牙槽骨之间的连接处：特别是 PrtP 脂蛋白蛋白酶复合物（dentilisin）和寡聚 Msp 蛋白。我们的总体假设是 dentilisin 和 Msp 是牙周病中 T. denticola 细胞病变行为的主要贡献者。 在上下文中，我们将检查 dentilisin 和 Msp 的特定域，以及 T. denticola 脂寡糖 外膜的组成部分。为了描述它们在微生物-宿主相互作用中的特定作用，我们 方法是利用纯化的天然和重组蛋白以及携带的同基因 T. denticola 菌株 这些外膜复合物的各个成分中确定的突变。我们将首先扩展我们的 正在进行的研究表征 Td 外膜中的牙菌素和 Msp 组装。然后，继续深造 宿主对 Td 及其特定成分的挑战的反应，然后我们将在细胞模型 T 中进行表征。 牙菌引起的 TLR/MyD88 和整合素/FAK 信号传导机制失调及其后果 细胞骨架以及基质金属蛋白酶的表达和活性。我们将确定范围 特定 T. denticola 成分导致小鼠组织破坏的机制 牙周病模型。最后，我们将测试抗菌肽乳链菌肽调节 T 的能力。 细胞和动物模型中齿菌诱导的菌群失调信号传导。我们的研究团队是独一无二的 定位于进行这些研究，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。该项目的完成将有利于双方 螺旋体分子生物学的基本知识以及慢性病中微生物与宿主相互作用的理解 牙周病等感染。