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.

项目总结/摘要 金博士参加了一个独特的牙周病学和牙科科学博士（DScD） 宾夕法尼亚大学牙科医学院的一个项目。在博兹博士的指导下- 巴塔利亚和顾问的支持下，金博士将研究细胞致死膨胀毒素（Cdt）介导的 调节吞噬功能。这一主题在牙周病学领域很重要，因为它将促进我们的 了解A.伴放线菌 调节局部宿主对局部侵袭性牙周炎（Localized aggressive periodontitis，BPH）的防御。金博士致力于 在学术方面，通过教育、技术和职业发展培训， 获得K 08奖。在宾夕法尼亚大学建立的专业/DScD计划将作为一个 这是金博士最终成为一名独立研究人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， 牙周炎的替代疗法。 在许多可能引起牙周炎的细菌中，Aa被认为是牙周炎的病原。我们 目前的理解是，Aa是为其他病原体提供合适环境的关键病原体， 因为...在Aa产生的不同类型毒素中，Kim博士的项目集中在Aa产生的Cdt 导致细胞周期停滞、T细胞凋亡和巨噬细胞中促炎细胞因子的上调 通过磷酸肌醇3-激酶阻断。CDT作为磷脂酰肌醇-3，4，5-三磷酸酶， 导致磷脂酰肌醇（PI）池失衡，这不仅对细胞反应至关重要， 降解Kim博士的首要假设是，Aa Cdt介导的巨噬细胞吞噬体的破坏 加工导致Aa存活，从而破坏局部宿主防御。在目标1中，金博士将研究 关于Cdt介导的PI库的具有效应蛋白的吞噬体成熟和吞噬-溶酶体融合 巨噬细胞失衡。在目标2中，Kim博士将通过以下方法研究Cdt对巨噬细胞和Aa存活能力的影响： 使用野生型和Cdt缺陷型突变体Aa。此外，金博士将研究促炎和 氧化应激与Aa的存活性有关。对于目标3，Kim博士将研究合成开环异落叶松树脂醇 二葡糖苷（LGM 2605），有效的自由基清除剂，抗氧化剂和抗炎剂，在减轻Aa 介导的炎症和骨丢失。总的来说，这些研究将进一步促进我们的 了解Aa在逃避吞噬作用和早期事件中的作用机制， 微生物生态失调此外，我们将扩大未来的治疗策略，为潜在的抗- 炎性因子