Novel anti-inflamatory lipid mediators

该项目的长期目标是基于对一些新型脂质衍生介质（LM）的作用模式的调节，开发新型白细胞功能调节剂作为抗炎分子。我们最近与Serhan博士的合作工作（项目1）导致了几种新的LM的鉴定和生物学研究，这些LM具有新颖和有前途的活性，包括脂氧素（LX），阿司匹林触发（ATL）和二磷酸前角鲨烯（PSDP）的几种生物稳定类似物。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，这涉及许多与炎症相关的其他细胞信号分子。根据最近的研究表明，这些LM在牙周病中的潜在参与，该项目旨在开发一系列新的分子，阐明它们的作用。因此，本项目将设计和合成：（1）LX和ATL的新结构类似物，以及（2）PSDP的新结构类似物。除了这些分子的合成和构象研究外，本项目还将寻求几种新的合成方法，以促进其合成。合成分子将用于本项目1-3的生物测定，并将为每种靶向LM建立结构-活性关系。最后，将选定的化合物按比例放大用于核心D（示范核心）中的体内动物模型研究。总的来说，该项目将导致几个局部活性LM的生理和病理生理作用的阐明，特别是在宿主防御和炎症。因此，这项研究可能会导致开发具有新的抗炎特性的新分子，其在调节组织介导的损伤（如牙周病）方面具有治疗潜力。

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.