Defining the role of sphingolipids on Porphyromonas gingivalis outer membrane vesicle uptake and elicited inflammation

定义鞘脂对牙龈卟啉单胞菌外膜囊泡摄取和引发炎症的作用

• 批准号: 10750635
• 负责人: Zavier G Eure
• 金额: $ 4.37万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-16 至 2025-08-15
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10750635
• 关键词: Adult; Affect; Age; Amino Alcohols; Anabolism; Award; Bacteria; Biological; Biomedical Research; Career Mobility; Cell Line; Cell model; Cells; Chemicals; Chemistry; Clinical; Clinical Data; Complex; Data; Deposition; Development; Disease; Elements; Fellowship; Florida; Future; Gingiva; Goals; Grant; Head; Health; Homeostasis; Human; Human Cell Line; Immune; Individual; Infection; Inflammation; Inflammatory Response; Investigation; Knowledge; Label; Learning; Link; Lipids; Macrophage; Measures; Mediating; Membrane; Methods; Microbe; Microscopy; Monitor; Mouth Diseases; Mus; Myelogenous; National Research Service Awards; Natural Immunity; Oral; Oral cavity; Organism; Outcomes Research; Parents; Pathway interactions; Periodontal Diseases; Periodontitis; Phosphorylation; Play; Porphyromonas gingivalis; Predisposition; Prevention approach; Process; Prokaryotic Cells; Proteins; Reporter; Research; Role; Route; Science; Secondary to; Signal Transduction; Sphingolipids; Stimulus; TLR2 gene; Techniques; Testing; Tissues; Toll-like receptors; Tooth Loss; Tooth structure; Training; Universities; Vesicle; Western Blotting; Work; base; bone loss; chronic inflammatory disease; defined contribution; dihydroceramide; dysbiosis; experimental study; immunoregulation; improved; inflammatory milieu; inhibitor; innate immune sensing; insight; matriculation; microbial; microorganism; morphogens; mutant; novel; oral bacteria; oral biology; pathobiont; pathogen; polymicrobial disease; pre-doctoral; programs; protein degradation; response; skills; subgingival microbiota; uptake

ABSTRACT The proposed work outlined in the training plan for this NRSA Individual Predoctoral Fellowships to Promote Diversity in Health-Related Research (F31) Award will support fourth year pre-doctoral candidate Zavier Eure throughout his graduate program at University of Florida. Mr. Eure has displayed phenomenal excellence in his academics and his learning of new lab techniques while being in the UF BMS program and currently supported by the Oral Biology Department R90/T90 Training Grant. The research and training plan for Mr. Eure will provide him a repertoire of skills needed to matriculate to the next level of his pre-doctoral training and also opportunities to further advance his career and professional development. Being awarded this F31 will offer Mr. Eure the ability to achieve his long-term goal of becoming a leader in science and provide a significant contribution to the field of biomedical research. Periodontal disease is a highly prevalent chronic inflammatory disease affecting up to 42% of adults in the US over the age of 30. Periodontal disease is orchestrated by various microorganisms that make up the subgingival microbiota. In susceptible individuals, dysbiosis of the subgingival microbiota promotes a dysregulated inflammation that causes an irreversible destruction of the soft and hard tissues supporting the teeth. Porphyromonas gingivalis (Pg) is an oral bacterium commonly associated with the microbial dysbiosis leading to periodontal disease. Pg is referred to as a pathobiont because its known to manipulate the host inflammatory milieu to facilitate disease states, however Pg can also remain in the oral cavity during healthy states. The various mechanisms behind how Pg contributes to the changing inflammatory milieu is yet to be identified. Our lab has discovered Pg sphingolipids (SLs) limit host inflammation and host cell SL transfer via outer membrane vesicles is a potential transport mechanism for Pg. The mechanism of OMV uptake by host cells is known to impact elicited inflammation and OMV composition (SL+ or SL-) plays an important role in the route for OMV uptake. Myeloid differentiation factor 88 (MyD88) is also known to be involved in the innate immune sensing of Pg OMVs and has been found to be a target for immunomodulation by Pg. I hypothesize Pg SLs facilitates an OMV uptake mechanism that limits inflammation and that SLs promote an immunomodulatory mechanism linked to targeting of MyD88. I plan to use the THP-1 human cell line and primary human macrophages to characterize the uptake mechanism of SL-containing Pg OMVs (Aim 1) and to determine the role of MyD88 in Pg SL-mediated immunomodulation (Aim 2).

摘要 NRSA个人博士前奖学金培训计划中概述的拟议工作，以促进 健康相关研究多样性奖(F31)将支持四年级博士前候选人泽维尔·尤尔 在他在佛罗里达大学的研究生课程期间。尤里先生在他的 学者和他在UF BMS项目中学习新的实验室技术，目前得到支持 口腔生物系R90/T90培训助学金。尤尔先生的研究和培训计划将提供 他掌握了进入下一阶段博士前培训所需的技能，同时也有机会 以进一步推进他的事业和职业发展。被授予这款F31将为尤尔先生提供 实现他成为科学领先者的长期目标，为该领域做出重大贡献 生物医学研究。 牙周病是一种高度流行的慢性炎症性疾病，在美国，高达42%的成年人受到影响 年龄在30岁以上。牙周病是由构成龈下组织的各种微生物共同作用的。 微生物区系。在易感个体中，龈下微生物区系的失调促进了一种失调的 对支撑牙齿的软硬组织造成不可逆转的破坏的炎症。 牙龈卟啉单胞菌(Pg)是一种常见的口腔细菌，与微生物的微生态失调有关 到牙周病。PG被称为致病素，因为它被认为是操纵宿主炎症的 然而，在健康状态下，PG也可以留在口腔内。这个 PG如何促进炎症环境变化背后的各种机制尚不清楚 确认身份。 我们的实验室已经发现PG鞘磷脂(SLS)可以抑制宿主炎症和宿主细胞SL通过外膜转移 膜泡是PG的一种潜在的转运机制。宿主细胞摄取OMV的机制是 已知影响引发的炎症和OMV成分(SL+或SL-)在致炎途径中发挥重要作用 OMV摄取。髓系分化因子88(MyD88)也参与了先天免疫反应。 并且被发现是PG免疫调节的靶点。我假设PG SLS有助于 抑制炎症的OMV摄取机制和SLS促进免疫调节机制 目标是MyD88。我计划使用THP-1人类细胞系和原代人类巨噬细胞来表征 含SL的PG OMvs摄取机制及MyD88在PG SL介导中的作用 免疫调节(目标2)。