Novel Mechanisms in Resolution to Harness Inflammation for Reconstruction

描述（由申请人提供）：该提案是为了响应RFA-DE-09-001而提交的，其总体目标是确定解决炎症的新成分，这些成分可用于控制局部炎症，并加速组织工程和患病和受伤口腔和颅面组织的再生。不受控制的局部炎症是包括牙周病（PD）在内的许多疾病的基础。我们已经发现了解决的新的基本途径，产生有效的专门的局部介质，既抗炎又促解决。这些被称为resolvins （Rv）的新局部介质家族提供了第一个证据，证明急性局部炎症的消退是一种主动的程序性反应，可以使组织恢复稳态。他们还介绍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。在伴有炎症引起的局部骨破坏的兔子牙周炎中，一种溶解蛋白，即溶解蛋白E1 (RvE1)，显示出有效的局部作用，可以减少炎症，防止骨质流失和刺激组织再生。这些结果令人鼓舞，因为它们表明溶解蛋白是内源性溶解程序的激动剂，可用于控制口腔炎症和组织损伤而不抑制免疫。为了实现RFA-DE-09-001的目标，一个多学科团队组成了一个具有互补技能的多学科团队，其重点任务是确定新的机制和成分，这些机制和成分可以设计用于控制颅面组织的炎症，以刺激再生和重建。在3个pi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；新的内源性炎症消退控制机制和成分的鉴定2. 利用溶解白细胞微粒构建新型促溶解药物（NPRM）3. 鉴定新型促溶解介质并在微流体室（MC）中设计工程化结构；4. 建立用于口腔再生和抗炎的牙周系统新溶解剂的性能；和5。评估NPRM系统对手术治疗的牙周病变局部递送促溶解激动剂的效果。这些目标集中在系统选择理想的“智能”NPRM结构，以刺激口腔炎症和组织再生的解决。提出的研究目标包括推进炎症自然消退和组织再生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。

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.