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).

抽象的 该NRSA个体培训培训计划中概述的拟议工作旨在促进 与健康相关研究的多样性（F31）奖将支持第四年的博士前候选人Zavier Eure 他在佛罗里达大学的整个研究生课程。 Eure先生在他的 在参加UF BMS计划时，学术界及其对新实验室技术的学习，目前支持 口腔生物学系R90/T90培训补助金。 Eure先生的研究和培训计划将提供 他的曲目曲目将入学到他的博士前培训的新水平以及机会 进一步促进他的职业和专业发展。被授予此F31将为Eure先生提供能力 实现他成为科学领导者并为该领域做出重大贡献的长期目标 生物医学研究。 牙周疾病是一种高度普遍的慢性炎性疾病，影响多达42％的美国成年人 30岁以上。牙周疾病由构成亚生物的各种微生物精心策划 微生物群。在敏感的个体中，尺寸菌群的营养不良会促进失调 炎症会导致支撑牙齿的软组织不可逆地破坏。 牙龈卟啉单胞菌（PG）是一种与微生物营养不良有关的口服细菌 致牙周病。 PG称为病原体，因为它已知可以操纵宿主炎症 促进疾病状态的环境，但是在健康状态下，PG也可以留在口腔中。这 PG如何促进不断变化的炎症环境背后的各种机制尚未 确定。 我们的实验室发现了PG鞘脂（SLS）限制宿主炎症和宿主细胞SL通过外部的转移 膜囊泡是PG的潜在运输机制。宿主细胞摄取OMV的机制是 已知会影响引起的炎症和OMV组成（SL+或SL-）在途径中起重要作用 OMV吸收。髓样分化因子88（MyD88）也参与了先天免疫感应 PG OMV的含量，已被发现是PG免疫调节的靶标。我假设PG SLS促进 限制炎症和SLS的OMV摄取机制促进了与免疫调节机制相关的 靶向myd88。我计划使用THP-1人类细胞系和主要人类巨噬细胞来表征 含SL的PG OMV的摄取机制（AIM 1），并确定MyD88在PG SL介导的作用 免疫调节（AIM 2）。