Novel Mechanisms in Resolution to Harness Inflammation for Reconstruction

描述（由申请人提供）：本提案是为了响应RFA-DE-09-001而提交的，总体目标是在炎症消退过程中识别可用于控制局部炎症并加速组织工程以及患病和受损口腔和颅面组织再生的新组分。不受控制的局部炎症是许多疾病的基础，包括牙周病（PD）。我们已经发现了新的基本途径的决议，产生强大的专门的地方调解人，既抗炎和pro-resolving。这些新的局部介质家族创造了消退素（Rv），提供了第一个证据表明急性局部炎症的消退是一种主动的程序化反应，使组织恢复稳态。他们还引入了一种治疗牙周病和其他炎症性疾病的新概念的范式转变。在伴有炎症诱导的局部骨质破坏的兔牙周炎中，Resolvin E1（RvE 1）具有有效的局部作用，可减少炎症，防止骨丢失和刺激组织再生。这些结果是令人鼓舞的，因为它们证明了消退素是内源性消退程序的激动剂，可用于控制口腔炎症和组织损伤，而无需免疫抑制。为了实现RFA-DE-09-001的目标，组建了一个多PI多学科团队，具有互补的技能，其重点使命是确定可用于控制颅面组织炎症以刺激再生并实现重建的新机制和组件。提出了三个PI及其实验室之间的五个多管齐下的具体目标。这些措施包括：1.确定新的内源性控制机制和组分在解决炎症; 2。从白细胞微粒（MP）中构建新型促消退药物（NPRM）; 3.在微流体室（MC）中鉴定新的促分解介质和设计工程化的构建体; 4.建立牙周系统中新的消退素用于口腔再生和抗炎的性质;和5.评价NPRM系统用于在体内向手术治疗的牙周病变局部递送促消退激动剂。这些目标集中于系统选择理想的“智能”NPRM构建体，用于刺激口腔炎症和组织再生的解决。拟议研究的目标包括推进炎症和组织再生中resolvins的自然消退中已知的分子和细胞机制，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：这项研究与公共卫生有关，因为过度炎症现在被认为是许多广泛发生的疾病（包括牙周病）的基础。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的促消退介质，激活炎症的消退，以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.