Novel anti-inflamatory lipid mediators

该项目的长期目标是开发新的白细胞功能调节剂，以作为抗炎分子，其基础是一些新型脂质衍生介质(LM)的作用方式的调节。我们最近与Serhan博士的合作(项目1)导致了几个新的LM的鉴定和生物学研究，这些新的LM具有新的和有前途的活性，包括几个生物稳定的脂氧素(LX)类似物、阿司匹林触发的(ATL)和前奎烯二磷酸(PSDP)。上述LM的一个典型特征是它们具有局部活性，并且它们具有多方面的生物活性，这涉及到许多与炎症相关的其他细胞信号分子。在最近的研究表明这些LM可能参与牙周疾病之后，这个项目试图开发一系列新的分子来阐明它们的作用。因此，本项目将致力于以下方面的设计和合成：(1)LX和ATL的新结构类似物，以及(2)PSDP的新结构类似物。除了对这些分子的合成和构象研究外，该项目还将寻求几种新的合成方法，以促进它们的合成。合成的分子将用于本计划项目1-3中的生物分析，并将为每个目标LM建立结构-活性关系。最后，选定的化合物将在核心D(示范核心)中放大用于体内动物模型研究。总体而言，该项目将有助于阐明几种局部活性的LM的生理和病理生理学作用，特别是在宿主防御和炎症方面。因此，这项研究可能导致开发具有新的抗炎特性的新分子，在调节组织介导性损伤方面具有治疗潜力，如在牙周病中。

The long-term goal of this project is the development of novel regulators of leukocyte function to serve as anti-inflammatory molecules based on the modulation of the mode of action of some new types of lipid-derived mediators (LM). Our recent collaborative work with Dr. Serhan (Project 1) has led to the identification and biological investigation of several new LM that have novel and promising activities, including several biostable analogues of the lipoxins (LX), the aspirin-triggered (ATL) and presqualene disphosphate (PSDP). A typical feature of the above LM is that they are topically active and that they have multi-faceted biological activity, which involves a number of other cell-signaling molecules related to inflammation. Following recent studies that suggested the potential involvement of these LM in periodontal diseases, this project seeks to develop a series of new molecules that would elucidate their role. Thus, this project will pursue the design and synthesis of: (1) new structural analogues of LX and ATL, and (2) new structural analogues of PSDP. In addition to synthetic and conformational studies of these molecules, this project will pursue several new synthetic approaches that may facilitate their synthesis. The synthetic molecules will be used in bioassays in Projects 1-3 of this program and structure-activity relationships will be established for each of the targeted LM. Finally, selected compounds will be scaled-up for in vivo animal model studies in Core D (Demonstration Core). Overall, this project will lead to the elucidation of the physiological and pathophysiological role of several topically active LM, particularly in host defense and inflammation. Therefore, this research may result in development of new molecules with novel anti-inflammatory properties with therapeutic potential in regulation of tissue-mediated injury, as in periodontal disease.