Resolution Mechanisms in Acute Inflammation: Resolution Pharmacology

 描述（由申请人提供）：当不受控制时，感染性炎症会损害器官功能，并与许多广泛发生的重大公共卫生问题的人类疾病有关。手术、创伤和组织损伤可使入侵的生物体引起感染和炎症，如果不解决，可能是致命的。这些屏障破坏和微生物入侵引起急性炎症，理想的是保护和自我解决。炎症的消退被认为是通过化学介质和促炎分子的被动稀释而发生的。从这个计划项目中，出现的证据表明，决议是一个积极的分子过程精心策划的新家庭的专门亲解决调解员（SPM）。这些结构上不同的家族包括消退素（Rv）、保护素（PD）、maresins（MaR）及其新发现的有效SPM-硫代-缀合物（SC），其消退炎症并刺激组织再生（Conjugates in Tissue Regeneration; CTR）。我们的总体使命在这个更新是系统地阐明结构和功能的新调解人的决议和组织再生。我们的战略计划包括脂质介质（LM）-SPM-代谢脂质组学，具有分辨率和再生指数，以询问炎症渗出物和组织，再加上SPM和SPM-SC标准品的全有机合成，以验证结构-功能。这个更新的每个项目要解决的首要新假设需要一个高度多学科的团队和方法。我们将共同测试以下内容：由组织损伤、手术创伤和感染引起的感染性炎性渗出物在局部释放有效的可溶性化学介质，如SPM及其新鉴定的硫代缀合物，这些化学介质积极协调炎症的消退，增强微生物的杀灭。 和清除，以及组织再生。这些新的分子解析程序对宿主防御至关重要，并决定了严重程度和恢复间隔。该计划项目团队被配置为解决这些未满足的挑战，由3个高度互动的项目，2个科学核心和一个管理核心组成，专家咨询小组专注于建立脂质介体解析功能代谢组，SPM的立体控制合成，SPM-SC及其在感染性炎症和清除途径中的特定机制。我们的广泛目标是利用这些分子和途径为新的治疗方法带来分辨率药理学，以控制感染性炎症和相关的组织损伤。

 DESCRIPTION (provided by applicant): When uncontrolled, infectious inflammation compromises organ function and is associated with many widely occurring human diseases of major public health concern. Surgery, trauma, and tissue injury can enable invading organisms to cause infections and inflammation that, if unresolved, can be fatal. These barrier breaks and microbial invasion evoke acute inflammation that is ideally protective and self-resolving. Resolution of inflammation was believed to occur via passive dilution of chemical mediators and pro-inflammatory molecules. From this Program Project, evidence emerged indicating resolution is an active molecular process orchestrated by new families of specialized pro-resolving mediators (SPM). These structurally distinct families include resolvins (Rv), protectins (PD), maresins (MaR) and their newly discovered potent SPM-sulfido-conjugates (SC) that resolve inflammation and stimulate tissue regeneration (Conjugates in Tissue Regeneration; CTR). Our overall mission in this renewal is to systematically elucidate the structures and functions of nove mediators in resolution and tissue regeneration. Our strategic plan includes lipid mediator (LM)-SPM-metabolipidomics with resolution and regeneration indices to interrogate inflammatory exudates and tissues coupled with total organic synthesis of SPM and SPM-SC standards to validate structure-function. The overarching novel hypothesis to be addressed by each project of this renewal requires a highly multi-disciplinary team and approach. Together, we shall test the following: Infectious inflammatory exudates evoked by tissue injury, surgical trauma and infection emit potent soluble chemical mediators locally such as SPM and their newly identified sulfido- conjugates that actively orchestrate resolution of inflammation, enhance microbial killing and clearance, as well as tissue regeneration. These new molecular resolution programs are essential for host defense and dictate severity and recovery intervals. This program project team is configured to address these unmet challenges and consists of 3 highly interactive projects, 2 scientific cores and an administrative core with expert advisory panels focused on establishing lipid mediator-resolution functional metabolome, stereo-controlled synthesis of SPM, SPM-SC and their specific mechanisms in resolution of infectious inflammation and clearance pathways. Our broad goal is to harness these molecules and pathways to bring forth resolution pharmacology for new treatments to control infectious inflammation and related tissue damage.