Resolution Mechanisms in Acute Inflammation: Resolution Pharmacology

 描述(申请人提供)：当不受控制时，感染性炎症损害器官功能，并与许多广泛发生的人类主要公共卫生问题疾病有关。手术、创伤和组织损伤可以使入侵的微生物引起感染和炎症，如果得不到解决，可能是致命的。这些屏障的破坏和微生物的入侵引起了急性炎症，这是理想的保护性和自我解决的。炎症的消退被认为是通过被动稀释化学介质和促炎分子来实现的。从这个计划项目中，有证据表明，拆分是一个由新的专门化前拆分介体(SPM)家族协调的活跃的分子过程。这些在结构上不同的家族包括溶血素(RV)、保护素(PD)、树脂素(MAR)及其新发现的有效的SPM硫代偶联物(SC)，它们可以消炎和刺激组织再生(Conjuates in Organization Regeneration；CTR)。我们在这次更新中的总体任务是系统地阐明nove介体在分解和组织再生中的结构和功能。我们的战略计划包括脂类介体(LM)-SPM-代谢脂组学，其分辨率和再生指数用于询问炎性渗出物和组织，并结合SPM和SPM-SC的全有机合成标准来验证结构功能。这次更新的每个项目都要解决总体上的新假设，这需要一个高度多学科的团队和方法。我们将共同测试以下几点：由组织损伤、手术创伤和感染引起的感染性炎症渗出物会在局部释放出有效的可溶性化学介质，如SPM及其新发现的硫代偶联物，它们能积极协调炎症的分解，增强微生物的杀灭作用。 和清除，以及组织再生。这些新的分子分辨程序对宿主防御至关重要，并规定了严重程度和恢复间隔。该计划项目团队旨在应对这些尚未解决的挑战，由3个高度互动的项目、2个科学核心和一个行政核心组成，其中有专家咨询小组，专注于建立脂类介体-拆分功能代谢组、SPM、SPM-SC的立体控制合成及其在消解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，为控制感染性炎症和相关组织损伤的新疗法带来分辨率药理学。

 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.