白色脂肪组织特异性核酸适体抑制成脂的分子机制及靶向治疗肥胖研究

Obesity is one of the most urgent diseases in modern medicine. There is no safe and effective way to treat it. It is a metabolic disorder characterized by excessive accumulation of white adipose tissue. It In the previous work, the applicant screened a nucleic acid suitable for the high affinity and high affinity of mature adipocytes and white adipose tissue with high affinity Adipo8. It is found that the aptamer has the function of inhibiting lipid formation and down regulating PPAR gamma in vivo and in vitro. It is preliminarily determined that the binding target of Adipo8 is membrane protein APMAP, which is closely related to lipid metabolism. It is suggested that in the differentiated mature adipocytes and white adipose tissue, Adipo8 can regulate the specific mRNA and protein level through binding with membrane protein APMAP, and down regulate the transcription of PPAR gene, which is the important gene of lipid metabolism, and inhibit the scientific hypothesis of lipid formation. The aim of this project is to further identify the target of Adipo8 as APMAP, determine the functional area of Adipo8 and APMAP, explore the molecular mechanism of inhibiting the biological function of adipocytes after binding with each other, and study the possibility of Adipo8 itself as a drug or probe as a target drug for the treatment of obesity. This project will provide a new theoretical basis and an effective molecular tool to elucidate the regulation of lipid metabolism and the development of obesity drugs.

肥胖是现代医学最亟待攻克的流行病之一，目前尚无治疗该病安全有效的方法。肥胖是以机体白色脂肪组织过度聚积为特征的代谢异常。申请者在前期工作中筛选到一条能与成熟脂肪细胞和白色脂肪组织高特异性高亲和力结合的核酸适体Adipo8。研究发现该核酸适体具有体内外抑制成脂及下调PPARγ的功能；初步确定Adipo8的结合靶标是与脂代谢密切相关的膜蛋白APMAP。据此提出在分化成熟的脂肪细胞和白色脂肪组织中，Adipo8通过与膜蛋白APMAP结合后调节胞内特定mRNA及蛋白水平，下调成脂重要基因PPARγ的转录从而抑制成脂的科学假说。本项目拟进一步鉴定Adipo8的靶标为APMAP；确定Adipo8和APMAP的功能区域，探讨二者结合后抑制成脂的生物学功能的分子机制；研究Adipo8本身作为药物或作为探针靶向载药治疗肥胖的可能性。本项目将为阐明脂代谢调控机制及肥胖药物的研发提供新的理论依据及有效的分子工具

肥胖是影响居民健康的重要因素之一，其主要病理生理特点在于机体白色脂肪组织过度聚积为特征的代谢异常。申请者在前期工作中筛选到一条能与脂肪细胞高特异性高亲和力结合的核酸适体Adipo8。基于Adipo8与脂肪细胞的高特异性及高亲和力这一特性，本项目主要聚焦于探索 Adipo8 通过与其靶标膜蛋白 APMAP 活性结构域结合后的一系列生物学功能，从而实现对成脂过程的抑制，同时，构建Adipo8靶向的白色脂肪组织的药物载体，实现对肥胖的靶向治疗。本研究首先筛选鉴定出APMAP是Adipo8的靶标蛋白，并初步探究了Adipo8利用茎环结构与APMAP的D306/N307位点结合，以及产生的一系列生物学效应，最终在细胞及动物层面证实了Adipo8作为功能性核酸适体，抑制了脂肪细胞成脂分化与脂质沉积。此外，构建出Adipo8-大黄素纳米颗粒，在细胞及动物水平探讨了Adipo8作为靶向载药工具在预防及治疗肥胖的作用，实现了功能性核酸适体-纳米药物双效治疗肥胖的作用，而同时不良反应较为轻微。本项目将为阐明脂代谢调控机制及肥胖药物的研发提供新的理论依据及有效的分子工具。