Oral Treponema Surface Proteins: Host Cell Interactions

口服密螺旋体表面蛋白：宿主细胞相互作用

基本信息

批准号：
9274236
负责人：
J CHRISTOPHER FENNO
金额：
$ 67.34万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9274236
关键词：
Affect Alveolar Bone Loss Animal Model Apoptosis Automobile Driving Behavior Binding Binding Proteins Biochemical Biological Assay Biology Calcium Cell Communication Cell Culture Techniques Cell Differentiation process Cell physiology Cell surface Cells Chronic Cleaved cell Complex Cytopathology Disease Environment Extracellular Matrix Fibronectins Gelatinase A Generations Genetic Gingiva Gingival Crevicular Fluid Goals Homeostasis Human Immune response Individual Infection Inflammation Inflammatory Knowledge Lead Lesion Lipoproteins Mediating Mediator of activation protein Membrane Membrane Proteins Molecular Analysis Molecular Biology Monitor Mutation Natural Immunity Nutrient Oral Order Spirochaetales Organism Parents Pathway interactions Pattern Penetration Peptide Hydrolases Periodontal Diseases Periodontal Ligament Periodontitis Porphyromonas gingivalis Positioning Attribute Process Proteins Recombinant Proteins Research Role Signal Transduction Surface Testing Tissues Tooth Socket Tooth structure Treponema Treponema denticola acquired immunity alveolar bone cytotoxic dentilisin experience genetic analysis genetic manipulation host-microbe interactions immunoregulation in vivo inhibitor/antagonist insight interest member microbiome migration mutant oral pathogen oral spirochetes osteoblast differentiation proMMP-2 protein complex protein expression protein protein interaction public health relevance response therapeutic target

项目摘要

DESCRIPTION (provided by applicant): The goal of this research is to characterize the role of Treponema denticola (Td) surface proteins in interaction of this human oral spirochete with host tissue, thereby gaining insight into mechanisms by which these organisms contribute to initiation and progression of periodontal disease. We focus on analysis of Td 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 Td cytopathic behavior in periodontal disease. To characterize their specific roles in microbe-host interactions, our approach is to utilize purified native and recombinant proteins as well as isogenic Td strains carrying defined mutations in individual components of these outer membrane complexes. We will first extend our ongoing studies characterizing dentilisin assembly in the Td outer membrane. Then, to further studies of host cell responses to Td challenge, we will (A) determine the mechanism of dentilisin-induced activation of pro-MMP-2 and (B) characterize MMP-2-dependent fibronectin fragmentation resulting from Td challenge of PDL cells. This project will test the hypothesis that dentilisin is an effector protein whose activity results in magnified "downstream" signaling effects that are likely to be significant in vivo. 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.

描述（由申请人提供）：本研究的目的是表征齿垢密螺旋体 (Td) 表面蛋白在人类口腔螺旋体与宿主组织相互作用中的作用，从而深入了解这些生物体促进启动和进展的机制我们重点分析直接影响从牙周膜 (PDL) 组织中分离出来的细胞的 Td 蛋白复合物，牙周膜是牙齿和牙槽骨之间的连接处。插座：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 Td 细胞病变行为的主要贡献者。利用纯化的天然和重组蛋白以及在这些外膜复合物的各个成分中携带确定突变的同基因 Td 菌株，我们将首先扩展我们正在进行的表征 dentilisin 的研究。然后，为了进一步研究宿主细胞对 Td 攻击的反应，我们将 (A) 确定牙菌素诱导的 pro-MMP-2 激活的机制，并 (B) 表征 MMP-2 依赖性纤连蛋白。该项目将测试牙菌素是一种效应蛋白的假设，其活性会导致放大的“下游”信号效应，这种效应在体内可能是独一无二的。结合螺旋体分子生物学、细胞外基质生物学和炎症性疾病细胞病理学方面的专业知识来开展这些研究，该项目的完成将有助于了解螺旋体分子生物学的基础知识，并有助于了解慢性感染中微生物与宿主的相互作用。牙周疾病。