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Novel Mechanisms in Resolution to Harness Inflammation for Reconstruction


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.

Funded by the NIH National Center for Advancing Translational Sciences through its Clinical and Translational Science Awards Program, grant number UL1TR002541.