Novel Mechanisms in Resolution to Harness Inflammation for Reconstruction

描述(申请人提供)：本提案是针对RFA-DE-09-001提出的，总体目标是确定炎症消退中可用于控制局部炎症的新成分，并加速组织工程和病变和受伤口腔和颅面组织的再生。失控的局部炎症是许多疾病的基础，包括牙周病(PD)。我们已经发现了解决问题的新的基本途径，这些途径产生了强大的专业本地调解人，既有抗炎作用，也有促进分解的作用。这些新的局部介质家族被称为解决素(RV)，这提供了第一个证据，表明急性局部炎症的消解是一种主动的程序性反应，使组织能够恢复内稳态。他们还引入了治疗牙周病和其他炎症性疾病的新概念的范式转变。在炎症诱导的局部骨质破坏的兔牙周炎中，一种解决素，即解决素E1(RvE1)，具有有效的局部作用，可减轻炎症，防止骨丢失和刺激组织再生。这些结果令人鼓舞，因为它们表明，分解素是内源性分解程序的激动剂，可用于控制口腔炎症和组织损伤，而不会抑制免疫。为了达到RFA-DE-09-001的目标，组建了一个多PI多学科团队，他们的技能互补，重点任务是确定新的机制和组件，这些机制和组件可以设计用于控制头面部组织的炎症，以刺激再生和实现重建。在3个绩效指标及其实验室中，提出了5个多管齐下的具体目标。这些包括：1.识别新的内源性控制机制和分解炎症的成分；2.从白细胞微粒(MP)中构建新的分解前药物(NPRM)；3.在微流体室(MC)中鉴定新的分解前介质和设计的结构；4.建立牙周系统中用于口腔再生和抗炎的新的分解素的性质；以及5.评价NPRM系统用于将促进分解的激动剂局部输送到手术治疗的活体牙周病变中。这些目的是为了系统地选择理想的“智能”NPRM结构，以刺激口腔炎症的消退和组织再生。拟议研究的目标包括推进已知的自然消炎的分子和细胞机制以及组织再生中的消解素，以及针对口腔炎症和颅面组织再生的新型生物工程天然模板设计策略的组装。 公共卫生相关性：这项研究与公共健康相关，因为过度炎症现在被认为是许多广泛发生的疾病的基础，包括牙周病(PD)。不受控制的炎症也阻碍了组织工程、再生和重建的努力。拟议的研究集中在新型促分解介质上，这些介质可以激活炎症的分解来控制炎症和组织再生。

DESCRIPTION (provided by applicant): This proposal is submitted in response to RFA-DE-09-001 with the overall goal of identifying novel components in the resolution of inflammation that can be used to control local inflammation and accelerate efforts in tissue engineering and regeneration of both diseased and injured oral and craniofacial tissues. Uncontrolled local inflammation underlies many diseases including periodontal disease (PD). We've uncovered novel fundamental pathways in resolution that generate potent specialized local mediators that are both anti-inflammatory and pro-resolving. These new families of local mediators coined resolvins (Rv) provided the first evidence that resolution of acute local inflammation is an active programmed response that enables tissues to return to homeostasis. They also introduced a paradigm shift with a novel concept for treating periodontal disease and other inflammatory diseases. In rabbit periodontitis with inflammation-induced local bone destruction, one resolvin, i.e., resolvin E1 (RvE1), exhibits potent topical actions reducing inflammation, protecting from bone loss and stimulating tissue regeneration. These results are encouraging because they demonstrate that resolvins are agonists of endogenous resolution programs that can be used to control oral inflammation and tissue damage without immune suppression. To meet the objectives for RFA-DE-09-001, a multi-PI multidisciplinary team is assembled with complementary skills with the focused mission of identifying novel mechanisms and components in resolution that can be designed for control of inflammation in craniofacial tissues to stimulate regeneration and enable reconstruction. Five multi-pronged specific aims are proposed among 3 PIs and their labs. These include: 1. The identification of novel endogenous control mechanisms and components in resolution-inflammation; 2. Construction of novel pro-resolving-medicines (NPRM) from resolving leukocyte microparticles (MP); 3. Qualify novel pro-resolving mediators and design-engineered constructs in microfluidics chambers (MC); 4. Establish properties of new resolvins in periodontal systems for oral regeneration and anti-Inflammation; and 5. Evaluate NPRM systems for local delivery of pro-resolving agonists to surgically treated periodontal lesions in vivo. These aims are focused for the systematic selection of ideal 'smart' NPRM constructs for stimulating resolution of oral inflammation and tissue regeneration. The objectives of the proposed studies include advancing the molecular and cellular mechanisms known in natural resolution of inflammation and resolvins in tissue regeneration as well as assembly of novel bioengineering natural template-design strategies targeted for oral inflammation and craniofacial tissue regeneration. PUBLIC HEALTH RELEVANCE: This research is relevant to public health because excessive inflammation is now recognized to underlie many widely occurring diseases including periodontal disease (PD). Uncontrolled inflammation also hampers efforts in tissue engineering, regeneration and reconstruction. The proposed studies focus on novel pro-resolving mediators that activate resolution of inflammation to control inflammation and tissue regeneration.