Cytolethal distending toxin mediated modulation of phagocytic function

点击翻译按钮获取中文摘要

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.