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.

项目摘要/摘要 金博士注册了一个独特的牙周学和牙科科学博士课程(DSCD) 宾夕法尼亚大学牙科医学院的项目。在博斯博士的指导下- 在巴塔格里亚和顾问的支持下，金博士将研究细胞致死膨胀毒素(CDT)介导的 吞噬功能的调节。这一主题在牙周学领域非常重要，因为它将促进我们的 伴放线放线菌产生CDT对其病理生理机制的认识 调节局部侵袭性牙周炎(LAP)的局部宿主防御。金博士致力于自己的事业 在学术方面，这将通过教育、技术和职业发展培训而大大加强 K08奖提供的机会。宾夕法尼亚大学已建立的专业/DSCD课程将作为 金博士的长期目标最终成为一名独立研究人员的重要垫脚石 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。 在许多可能导致牙周炎的细菌中，AA被认为是LAP的病原学。我们的 目前的理解是，AA是一种关键的病原体，为其他病原体和 因为要跑一圈。在AA产生的不同类型的毒素中，Kim博士的项目重点是AA产生的CDT 它导致细胞周期停滞，T细胞凋亡，并上调巨噬细胞中的促炎细胞因子 由磷脂酰肌醇3-激酶阻断。CDT是一种磷脂酰肌醇-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，对吞噬小体也是如此 退化。Kim博士的主要假设是AA CDT介导的巨噬细胞吞噬小体的破坏 处理导致AA存活，从而破坏当地寄主防御。在Aim1，金博士将调查 CDT介导的PI池的效应蛋白吞噬小体成熟和吞噬-溶酶体融合 巨噬细胞失衡。在目标2中，Kim博士将通过以下方式研究CDT对巨噬细胞和AA存活率的影响 利用野生型和CDT缺失突变体AA。此外，金博士将调查促炎症和 氧化应激与再生障碍性贫血存活率的关系。对于目标3，金博士将研究合成的次异构烷基树脂醇 二葡糖苷(LGM2605)是一种有效的自由基清除剂、抗氧化剂和消炎剂，可缓解再生障碍性贫血 通过体内和体外介导炎症和骨丢失。总的来说，这些研究将进一步推动我们的 了解AA在逃避吞噬和早期事件中的作用机制 微生物生态失调。此外，我们将扩展未来的治疗LAP的策略，具有潜在的抗 发炎剂。