Programming dendritic cells in concert with morphagen delivery for periodontal re

描述(申请人提供)：慢性炎症是牙周炎的主要组成部分，虽然已经确定了几种组织工程和再生策略，这些策略可能能够逆转牙周炎的破坏性影响，但它们的有效性可能会受到慢性炎症状态的有害微环境特征的影响。树突状细胞(DC)是免疫系统的传导者，可以提供适当的靶点来操纵和重定向免疫反应，以提供非炎症性和非破坏性的局部环境。这一应用是基于这样一个假设，即提供适当时空提示的材料系统可以局部控制DC的激活，以便将免疫反应偏向非炎症性表型，并显著增强同一材料系统携带的骨诱导分子的有效性。这一假说将被验证有以下一组特定的目标：(1)将开发材料系统来招募宿主DC并促进其激活以达到非炎症表型，(2)检测招募并编程大量耐受树突状细胞的材料在牙周炎啮齿动物模型中促进调节性T细胞分化和介导炎症的能力，以及(3)编码BMP-2的质粒DNA将从抑制炎症的材料系统中被输送，以测试通过DC靶向减少炎症是否可以增强诱导方法在牙周炎啮齿动物模型中再生牙槽骨的有效性。这些目标的成功完成将提供新的材料，其功能是首先调节炎症驱动的牙周病进展，然后在成功抑制炎症后积极促进再生。我们设想，这些研究产生的材料和知识可以很容易地转化为新的材料，用于引导组织再生(GTR)，积极调节局部免疫和原位组织重建细胞群。更广泛地说，炎症是牙科和医学中许多其他临床挑战的组成部分，该项目中追求的一般策略可能在治疗许多以炎症介导的组织破坏为特征的疾病方面具有广泛的实用价值。此外，这些材料系统还可能为探索DC运输、激活、T细胞分化以及免疫系统和炎症之间的关系的基础研究提供新的和有用的工具。 公共卫生相关性：牙周病困扰着数百万美国人。既能阻止这种疾病的慢性炎症，又能促进丢失的骨组织再生的新疗法，可能会让许多这样的患者受益。

DESCRIPTION (provided by applicant): Chronic inflammation is a major component of periodontitis, and while several tissue engineering and regeneration strategies have been identified that may be able to reverse the destructive effects of periodontitis their utility is likely compromised by the hostile microenvironment characteristic of the chronic inflammatory state. Dendritic cells (DCs) are the conductors of the immune system, and they may provide an appropriate target to manipulate and redirect the immune response to provide a non-inflammatory and non-destructive local environment. This application is based on the hypothesis that a material system providing appropriate spatiotemporal presentation of cues can locally control DC activation in order to bias the immune response towards a non-inflammatory phenotype, and dramatically enhance the effectiveness of bone inducing molecules carried by the same material system. This hypothesis will be examined with the following set of specific aims: (1) Materials systems will be developed to recruit host DCs and promote their activation towards a non-inflammatory phenotype, (2) Examine the ability of materials that recruit and program large numbers of tolerogenic DCs to promote regulatory T-cell differentiation and mediate inflammation in rodent models of periodontitis, and (3) Plasmid DNA encoding BMP-2 will be delivered from the material system that suppresses inflammation, to test whether reducing inflammation via DC targeting can enhance the effectiveness of inductive approaches to regenerate alveolar bone in rodent models of periodontitis. Successful completion of these aims will provide new materials that function to first modulate the inflammation-driven progression of periodontal disease, and then actively promote regeneration after successful suppression of inflammation. We envision the material and knowledge resulting from these studies can readily be translated into new materials for guided tissue regeneration (GTR) that actively regulate local immune and tissue rebuilding cell populations in situ. More broadly, inflammation is a component of many other clinical challenges in dentistry and medicine, and the general strategy pursued in this project could have wide utility in treating many of these diseases characterized by inflammation-mediated tissue destruction. Further, the material systems are also likely to provide novel and useful tools for basic studies probing DC trafficking, activation, T-cell differentiation, and the relation between the immune system and inflammation. PUBLIC HEALTH RELEVANCE: Periodontal disease afflicts millions of Americans. New therapies that can both stop the chronic inflammation characterizing this disease, and subsequently promote regeneration of the lost bone tissue could benefit many of these patients.