PKCα/PPARγ介导TAMs代谢重编程及其对肿瘤微环境炎性的调控

项目名称： PKCα/PPARγ介导TAMs代谢重编程及其对肿瘤微环境炎性的调控

项目编号： No.81473220

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 沈萍萍

作者单位： 南京大学

项目金额： 90万元

中文摘要： 肿瘤相关巨噬细胞(TAMs)具有独特功能模式，对肿瘤微环境炎性进展起决定性作用，但与TAMs功能相关的代谢途径与编程调控机制尚不明确。本项目将基于前期工作中的重要发现，开展以下工作：1.在分子、细胞、动物水平对TAMs代谢模式进行研究，建立TAMs代谢重编程与其调控肿瘤微环境炎性功能之间的确切联系；2.在解析PKCα介导PPARγ 186Ser磷酸化修饰机理的基础上，揭示PKCα/PPARγ分子相互作用界面对TAMs代谢途径的调控效应；3.通过干预PKCα/PPARγ介导的代谢通路，诠释靶向调控TAMs代谢重编程而遏制肿瘤微环境恶性炎症的可行性。4. 运用分子、细胞、动物筛选体系，对小分子靶向TAMs代谢重编程的效应进行评价。通过本项目研究，将提出TAMs代谢重编程的相关机制、PKCα介导PPARγ186Ser磷酸化修饰的新概念，并为治疗肿瘤、恶性炎症及相关疾病提供新的干预靶标与候选药物。

中文关键词： 肿瘤相关巨噬细胞；PKCα/PPARγ；代谢重编程；肿瘤微环境炎性；分子靶向

英文摘要： Tumor-associated macrophages (TAMs) are cells with unique functionalities, playing the significant role in the inflammatory progression in tumor microenvironment; However, the mechanistic understanding on TAMs' metabolic pathway and regulatory programming mechanisms remains elusive. Based on the results from our previous studies, aiming to solve the issues, the current project will perform the following research: 1) the TAMs metabolic pattern will be studied at the levels of molecule, cell and animal model, which will establish the meaningful link between TAMs's metabolic reprogramming and the inflammatory progression in the tumor microenvironment regulated by TAMs; 2) Based on revealing the Ser186-PPARγ phosphorylation mechanism via PKCα, we will further elucidate the critical role of protein-protein interaction between PKCα/PPARγ in TAMs's metabolic process; 3) By interfering with the PKCα/PPARγ mediated metabolic pathway, we will study the possibility of suppressing the detrimental inflammation in tumor micro-environment by targeting TAMs metabolic reprogramming; 4) By using screening system, we will evaluate the effects of small molecules-targeting on TAMs metabolic reprogramming at the levels of molecule, cell and animal. Conclusively, we are here proposing to comprehensively understand the TAMs metabolic reprogramming mechanism, the novel phosphorylation mechanism on Ser186-PPARγ via PKCα, which will provide the new therapeutical options and drug candidates for treating tumor，its associated adverse inflammation and the related diseases.

英文关键词： Tumor-associated macrophages;PKCα/PPARγ;Metabolic reprogramming;Inflammatory status of tumor microenvironment;Molecular targeted treatment