P.gingivalis interactions with gingival epithelial cells

牙龈卟啉单胞菌与牙龈上皮细胞的相互作用

• 批准号: 8984161
• 负责人: Richard J Lamont
• 金额: $ 37.5万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8984161
• 关键词: Actins; American; Bacterial Infections; Binding; Biological; Biological Assay; CXCL10 gene; Cell Communication; Cells; Complement; Data; Development; Disease; Elements; Ensure; Epithelial Cells; Equilibrium; Family; Generations; Gingiva; Goals; Health Status; Healthcare Systems; Human; I-kappa B Proteins; IL8 gene; IRF1 gene; Immune; Immunologic Surveillance; Infection; Instruction; Interferons; Knowledge; LIM Domain Kinase 1; LIMK1 gene; Label; Lead; Location; Luciferases; MEK inhibition; MEKs; Measurement; Measures; Mediating; Microbe; Molecular; Molecular Analysis; Natural Immunity; Nuclear Translocation; Oral cavity; Organism; Outcome; Pathway interactions; Periodontal Diseases; Phospho-Specific Antibodies; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Plasmids; Porphyromonas gingivalis; Process; Production; Protein Dephosphorylation; Proteins; ROCK1 gene; Regulation; Reporter; Role; Serine; Signal Transduction; Signal Transduction Pathway; Signaling Molecule; Small Interfering RNA; Structure; T-Lymphocyte; TNF gene; Testing; Therapeutic Agents; Variant; actin depolymerizing proteins; cell motility; chemokine; cofilin; design; in vivo; live cell imaging; mutant; novel; novel therapeutics; overexpression; p65; pathogen; prevent; promoter; response; transcription factor

Periodontal diseases are one of the most common bacterial infections of humans and impose a significant burden on the health care system. One of the predominant pathogens in periodontal disease is P. gingivalis; however, P. gingivalis can also inhabit the oral cavity in the absence of disease. The interaction between P. gingivalis and gingival epithelial cells makes a significant contribution to the degree of equilibrium between host and microbe, and to overall gingival health status. P. gingivalis can manipulate epithelial cell signal transduction pathways in order to direct entry into the host cell and to reprogram host innate immunity. One of the effector molecules of P. gingivalis is the HAD family serine phosphatase, SerB. The goal of this proposal is define the outcomes of the interaction between P. gingivalis and gingival epithelial cells as they relate colonization of the organism and the generation of immune dysbiosis. We shall also continue our major focus on the role of the functionally versatile SerB invasin and modulin of P. gingivalis. Cofilin, an actin depolymerizing protein, is required for P. gingivalis invasion. We will examine the ability of SerB to dephosphorylate and inactivate LIMK kinase which will lead to activation of cofilin. We will then investigate the impact of P. gingivalis on ROCK, PAK1 and MK2 pathways that lead to activation of LIMK. These interactions will be observed within the cell by live cell imaging. P..gingivalis can suppress IL-8 production in part through regulation of actin dynamics. We shall study the cofilin dependent, actin mediated suppression of IL-8 by P. gingivalis. The immune disruptive ability of P. gingivalis also extends to T-cell chemokines, and the mechanism of suppression of IP-10, ITAC and Mig will be studied. We will also begin to assess biological relevance by examining T-cell migration in response to epithelial cells infected with P. gingivalis. These studies will provide a detailed molecular analysis of the targeting of host signal transduction by P. gingivalis along with the role of a specific effector phosphatase. Ultimately, the knowledge gained could be developed into strategies that could be utilized to intervene in the P. gingivalis-epithelial cell interaction to ensure that the outcome is non-harmful to the host.

牙周病是人类最常见的细菌感染之一，对人类造成重大影响。 医疗保健系统的负担。牙周病的主要病原体之一是 P. 牙龈;然而，在没有疾病的情况下，牙龈卟啉单胞菌也可以栖息在口腔中。互动 牙龈卟啉单胞菌和牙龈上皮细胞之间的相互作用对牙龈卟啉单胞菌的程度做出了重大贡献 宿主和微生物之间的平衡以及整体牙龈健康状况。牙龈卟啉单胞菌可以操纵 上皮细胞信号转导途径，以直接进入宿主细胞并重新编程宿主 先天免疫。牙龈卟啉单胞菌的效应分子之一是 HAD 家族丝氨酸磷酸酶 SerB。 该提案的目标是定义牙龈卟啉单胞菌和牙龈之间相互作用的结果 上皮细胞，因为它们与生物体的定植和免疫失调的产生有关。我们将 我们还将继续重点关注功能多样的 SerB 侵袭素和 P 调节蛋白的作用。 牙龈。 Cofilin 是一种肌动蛋白解聚蛋白，是牙龈卟啉单胞菌入侵所必需的。我们将检查 SerB 去磷酸化和灭活 LIMK 激酶的能力，这将导致丝切蛋白的激活。我们 然后将研究牙龈卟啉单胞菌对 ROCK、PAK1 和 MK2 途径的影响，从而导致激活 林克。这些相互作用将通过活细胞成像在细胞内观察到。牙龈卟啉单胞菌可以抑制 IL-8 的产生部分是通过调节肌动蛋白动力学来实现的。我们将研究丝切蛋白依赖的肌动蛋白 牙龈卟啉单胞菌介导的 IL-8 抑制。牙龈卟啉单胞菌的免疫破坏能力还延伸到 将研究T细胞趋化因子以及IP-10、ITAC和Mig的抑制机制。我们也会 开始通过检查对上皮细胞感染的反应的 T 细胞迁移来评估生物学相关性 与牙龈卟啉单胞菌。这些研究将为宿主信号的靶向提供详细的分子分析 牙龈卟啉单胞菌的转导以及特定效应磷酸酶的作用。最终， 获得的知识可以发展成可用于干预 P 的策略。 牙龈-上皮细胞相互作用，以确保结果对宿主无害。