Cytolethal distending toxin mediated modulation of phagocytic function

细胞致死膨胀毒素介导的吞噬功能调节

• 批准号: 10507107
• 负责人: Taewan John Kim
• 金额: $ 7.46万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10507107
• 关键词: Actinobacillus actinomycetemcomitans; Anti-Inflammatory Agents; Antiinflammatory Effect; Antioxidants; Apoptosis; Award; Bacteria; Bone remodeling; Cell Cycle Arrest; Cells; Colony-forming units; Connective Tissue; Dental Schools; Dentistry; Diphosphates; Disease; Disease model; Effectiveness; Endocytosis; Endosomes; Enrollment; Environment; Etiology; Event; Free Radical Scavengers; Future; Gingiva; Goals; Host Defense; Human; Immune response; Immune system; Immunotoxins; In Vitro; Incisor; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Lead; Measures; Mediating; Medicine; Membrane; Mentorship; Modeling; Organism; Oxidative Stress; Pathogenesis; Pathologic; Pattern; Pennsylvania; Periodontal Ligament; Periodontic specialty; Periodontitis; Periodontium; Phagocytes; Phagocytosis; Phagolysosome; Phagosomes; Phosphatidylinositols; Phosphoric Monoester Hydrolases; Phosphotransferases; Play; Pre-Clinical Model; Process; Production; Proteins; Reactive Oxygen Species; Research Personnel; Role; Science; Signal Transduction; Structure; T-Lymphocyte; Testing; Therapeutic; Therapeutic Intervention; Tooth Loss; Tooth structure; Toxin; Universities; Virulence Factors; alveolar bone; bone loss; career; career development; chronic inflammatory disease; cytokine; cytolethal distending toxin; dysbiosis; experimental study; holotoxins; in vivo; innovation; macrophage; medical specialties; microbial; microbicide; microbiota; monocyte; mouse model; mutant; novel; novel therapeutic intervention; osteoclastogenesis; pathogen; programs; recruit; response; secoisolariciresinol; small molecule therapeutics; spatiotemporal; trafficking; training opportunity; tripolyphosphate

Project Summary/Abstract Dr. Kim is enrolled in a uniquely combined periodontics and Doctor of Science in Dentistry (DScD) program at the University of Pennsylvania School of Dental Medicine. Under the mentorship of Dr. Boesze- Battaglia and support from consultants, Dr. Kim will investigate cytolethal distending toxin (Cdt) mediated modulation of phagocytic function. This topic is important in the field of periodontology as it will advance our understanding of the pathophysiological mechanism by Cdt produced by A. actinomycetemcomitans (Aa) modulates local host defense regarding localized aggressive periodontitis (LAP). Dr. Kim is committed to a career in academics, which will be greatly enhanced by the educational, technical and career development training opportunities afforded by the K08 Award. The established specialty/DScD program at Penn will serve as an important stepping stone for Dr. Kim's long-term goal to eventually emerge as an independent researcher studying the pathophysiological mechanism of bacterial and host immune response in an effort to develop adjunctive/alternative therapeutics for periodontitis. Among many possible bacteria that can cause periodontitis, Aa was known as the etiology for LAP. Our current understanding is that Aa is a critical pathogen providing a suitable environment for other pathogens and cause LAP. Among different types of toxins produced by Aa, Dr. Kim's project focus on Cdt produced by Aa which causes cell cycle arrest, apoptosis in T cells and upregulates pro-inflammatory cytokines in macrophages by phosphoinositide 3-kinases blockade. Cdt acts as a phosphatidylinositol-3,4,5-triphosphate phosphatase and causes phosphatidylinositol (PI) pool imbalance which is crucial for not only the cellular response but phagosome degradation. Dr. Kim's overarching hypothesis is that Aa Cdt-mediated disruption in macrophage phagosome processing leads to Aa survival contributing to disruption of local host defense. In Aim1, Dr. Kim will investigate phagosome maturation with effector proteins and phago-lysosome fusion regarding Cdt-mediated PI pool imbalance in macrophage. In Aim 2, Dr. Kim will study effect of Cdt on macrophage and survivability of Aa by using wild type and Cdt deficient mutant Aa. Furthermore, Dr. Kim will investigate the pro-inflammatory and oxidative stress in relation to survivability of Aa. For aim 3, Dr. Kim will investigate synthetic secoisolariciresinol diglucoside (LGM2605), potent free radical scavenger, antioxidant, and anti-inflammatory agent, in mitigating Aa mediated inflammation and bone loss via in vivo and in vitro. Collectively, these studies will further our understanding of the mechanisms underlying the role of Aa in the evasion of phagocytosis and early events in microbial dysbiosis. Moreover, we will expand future therapeutic strategy for LAP with a potential anti- inflammatory agent.

项目概要/摘要 Kim 博士就读于牙周病学和牙科科学博士 (DScD) 的独特组合 宾夕法尼亚大学牙科医学院的计划。在Boesze博士的指导下- 在 Battaglia 和顾问的支持下，Kim 博士将研究细胞致死膨胀毒素 (Cdt) 介导的 吞噬功能的调节。这个主题在牙周病学领域很重要，因为它将推进我们的研究 了解 A. actinomycetemcomitans (Aa) 产生的 Cdt 的病理生理机制 调节局部侵袭性牙周炎 (LAP) 的局部宿主防御。金博士致力于事业 学术方面，通过教育、技术和职业发展培训将大大提高 K08 奖提供的机会。宾夕法尼亚大学已建立的专业/DScD 项目将作为 金博士最终成为一名独立研究员的长期目标的重要垫脚石 研究细菌和宿主免疫反应的病理生理机制，努力开发 牙周炎的辅助/替代疗法。 在许多可能引起牙周炎的细菌中，Aa 被认为是 LAP 的病因。我们的 目前的认识是，Aa 是一种重要的病原体，为其他病原体提供了合适的环境，并且 引起LAP。在 Aa 产生的不同类型的毒素中，Kim 博士的项目重点关注 Aa 产生的 Cdt 导致细胞周期停滞、T 细胞凋亡并上调巨噬细胞中的促炎细胞因子 通过磷酸肌醇 3-激酶阻断。 Cdt 充当磷脂酰肌醇-3,4,5-三磷酸磷酸酶， 导致磷脂酰肌醇 (PI) 池失衡，这不仅对细胞反应至关重要，而且对吞噬体也至关重要 降解。 Kim 博士的总体假设是 Aa Cdt 介导的巨噬细胞吞噬体破坏 加工导致 Aa 存活，从而破坏本地宿主防御。在 Aim1 中，Kim 博士将进行调查 与 Cdt 介导的 PI 池相关的效应蛋白吞噬体成熟和吞噬溶酶体融合 巨噬细胞失衡。在目标 2 中，Kim 博士将研究 Cdt 对巨噬细胞和 Aa 存活率的影响 使用野生型和 Cdt 缺陷突变体 Aa。此外，金博士将研究促炎和 氧化应激与 Aa 的生存能力有关。对于目标 3，Kim 博士将研究合成开环异落叶松树脂醇 二葡萄糖苷 (LGM2605)，有效的自由基清除剂、抗氧化剂和抗炎剂，可减轻 Aa 通过体内和体外介导炎症和骨质流失。总的来说，这些研究将进一步推动我们 了解 Aa 在逃避吞噬作用和早期事件中的作用的机制 微生物失调。此外，我们将扩展 LAP 的未来治疗策略，并具有潜在的抗 炎症剂。