Controlled antibiotic delivery vehicle for treatment of aggressiveperiodontitis

项目摘要/摘要 伴伴放线杆菌(AA)的侵袭性牙周炎通常比较困难。 采用传统方法(洁治、根面平整，联合全身抗生素)治疗。在.期间 感染，再生障碍性贫血会产生一种白细胞毒素(LtxA)，杀死宿主免疫细胞，从而降低宿主清除 感染。尽管在再生障碍性贫血的致病力与LtxA的表达水平之间存在良好的相关性 有记录，特别是在青少年患者中，以及LtxA杀死宿主细胞的机制一直是 经过充分研究，近年来很少有新的治疗方案被开发出来。我们建议，Ltd.A代表 一种理想的治疗靶点，可用于开发下一代治疗再生障碍性贫血感染的药物 青少年。 PI的长期目标是开发针对再生障碍性贫血的治疗方法。总体目标 该项目的目的是构建一种脂质体为基础的、对LtxA有反应的抗生素递送载体，以治疗AA感染。 一般的假设是，只有在存在致病物质的情况下，LtxA才能使抗生素释放。 表达)菌株。一般假设将通过以下具体目标进行检验：(1)优化 脂质体组合物促进LtxA的吸附和LtxA介导的破坏和(2)确定 提高宿主细胞存活率所需的治疗性脂质体浓度。在目标1中，我们将优化 脂质体的组合物，以促进LtxA介导的抗生素释放和LtxA的吸附。在目标2中，我们将 在共培养感染模型中测试脂质体对宿主细胞存活的影响。在成功的 完成拟议的研究，预期结果是治疗再生障碍性贫血感染的新的治疗选择 在青少年中。这项拟议工作的创新之处在于它使用LtxA作为治疗靶点，以及 用于治疗侵袭性牙周炎的抗生素控释载体的开发。这些结果 将为以LtxA为重点的疗法的未来发展提供坚实的基础，预计将有 为青少年AA相关感染的临床治疗提供额外的、非 手术选择。这项研究与NIDCR的使命一致，即通过开发一种 牙周感染的新疗法。

PROJECT SUMMARY/ABSTRACT Aggressive forms of periodontitis associated with Aggregatibacter actinomycetemcomitans (Aa) are often difficult to treat with traditional means (scaling and root planing, in combination with systemic antibiotics). During infection, Aa produces a leukotoxin (LtxA) that kills host immune cells, thus reducing the host’s ability to clear the infection. Although an association between LtxA expression levels and pathogenicity of Aa has been well documented, particularly in adolescent patients, and the mechanisms by which LtxA kills host cells have been well studied, few new treatment options have been developed in recent years. We propose that LtxA represents an ideal therapeutic target that could be exploited to develop next generation therapeutics for Aa infections in juveniles. The long-term goal of the PI is to develop LtxA-focused therapeutics for the treatment of Aa. The overall objective of this project is to construct a liposome-based, LtxA-responsive antibiotic delivery vehicle to treat Aa infections. The general hypothesis is that LtxA will enable antibiotic release only in the presence of pathogenic (LtxA- expressing) strains of Aa. The general hypothesis will be tested via the following specific aims: (1) Optimize liposome composition to promote LtxA adsorption and LtxA-mediated disruption and (2) Determine the therapeutic liposome concentrations necessary to enhance host cell survival. In Aim 1, we will optimize the composition of the liposome to enhance LtxA-mediated antibiotic release and LtxA adsorption. In Aim 2, we will test the effect of the liposomes on host cell survival in a co-culture model of infection. At the successful completion of the proposed research, the expected outcome is a novel therapeutic option to treat Aa infections in adolescents. The innovation of the proposed work lies in its use of LtxA as a therapeutic target, as well as the development of a controlled antibiotic delivery vehicle for the treatment of aggressive periodontitis. These results will provide a strong basis for the future development of LtxA-focused therapeutics, which is expected to have a significant impact on the clinical treatment of Aa-associated infections in juveniles by providing additional, non- surgical options. This research aligns with NIDCR’s mission to improve oral health through its development of a new treatment for periodontal infections.