Novel Mechanisms in Resolution to Harness Inflammation for Reconstruction

利用炎症进行重建的解决新机制

• 批准号: 8073173
• 负责人: Daniel Irimia
• 金额: $ 64.35万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-17 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8073173
• 关键词: Acute; Agonist; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Biomedical Engineering; Bone Regeneration; CD59 Antigen; Cell Culture Techniques; Cells; Coin; Coupled; Dental Cementum; Disease; Engineering; Evaluation; Event; Exhibits; Exudate; Family; Fibroblasts; Goals; Healed; Homeostasis; Human; Immunosuppression; Immunosuppressive Agents; In Vitro; Inflammation; Inflammatory; Lesion; Leukocytes; Mediator of activation protein; Medicine; Microfluidics; Miniature Swine; Mission; Molecular; Mus; Natural regeneration; Oral; Oryctolagus cuniculus; Pathway interactions; Periodontal Diseases; Periodontal Ligament; Periodontitis; Placebos; Process; Property; Public Health; Qualifying; Research; Resolution; Role; System; Time; Tissue Engineering; Tissues; Wound Healing; analog; base; bone; bone loss; craniofacial; design; engineering design; healing; in vivo; indexing; inhibitor/antagonist; injured; meetings; monocyte; multidisciplinary; neutrophil; novel; programs; public health relevance; reconstruction; response; skills; tissue regeneration

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.

描述（由申请人提供）：本提案是针对 RFA-DE-09-001 提交的，总体目标是确定解决炎症的新成分，可用于控制局部炎症并加速组织工程和再生的努力患病和受伤的口腔和颅面组织。不受控制的局部炎症是包括牙周病 (PD) 在内的许多疾病的根源。我们发现了新的消退基本途径，可以产生有效的、具有抗炎作用和促消退作用的专门局部介质。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性反应，可以使组织恢复稳态。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。在炎症引起的局部骨破坏的兔牙周炎中，一种 resolvin，即 resolvin E1 (RvE1)，表现出有效的局部作用，可减少炎症、防止骨质流失并刺激组织再生。这些结果令人鼓舞，因为它们证明消解素是内源性消解程序的激动剂，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，一个多 PI 多学科团队组成了具有互补技能的团队，其重点任务是确定解决方案中的新机制和组件，这些机制和组件可设计用于控制颅面组织炎症以刺激再生并启用重建。三位 PI 及其实验室提出了五个多管齐下的具体目标。这些包括： 1. 确定炎症消退中的新型内源性控制机制和成分； 2. 利用分解白细胞微粒（MP）构建新型促分解药物（NPRM）； 3. 鉴定微流体室（MC）中新型促解析介质和设计工程结构； 4. 建立牙周系统中新型消解素的特性，用于口腔再生和抗炎； 5. 评估 NPRM 系统向体内手术治疗的牙周病变局部递送促溶解激动剂的情况。这些目标的重点是系统地选择理想的“智能”NPRM 结构，以刺激口腔炎症的解决和组织再生。拟议研究的目标包括推进炎症自然消退和组织再生消退素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自然模板设计策略的组装。 公共健康相关性：这项研究与公共健康相关，因为过度炎症现在被认为是包括牙周病 (PD) 在内的许多广泛发生的疾病的基础。不受控制的炎症也会阻碍组织工程、再生和重建的努力。拟议的研究重点是新型促消退介质，可激活炎症消退以控制炎症和组织再生。