靶向脂肪组织血管新生并pH控释Irisin分子探针的构建及其评价白色脂肪棕色化过程的多模态MR研究

Activation of browning of white adipose tissue may play an important role in prevention and therapy of obisity and metabolic syndrome. There is a strong relationship among irisin, the adipose tissue angiogenesis and browning of white adipose tissue. Irisin is secreted as a newly identified hormone from the muscle to circulation and acts on white adipose cell to promote browning of white adipose tissue. However, it is still unclear about the irisin-mediated exact mechanisms in adipose tissue angiogenesis and browning of white adipose tissue. It is urgently needed to search imaging biomarker and MR imaging methods to enable non-invasive accurate detection of the procession of browning of white adipose tissue. However, such imaging techniques are not still established. Thus, to dynamically demonstrate the relations and potential mechanisms among the Irisin, angiogenesis and browning of white adipose tissue, we plan to design and synthesize the novel probe that has RGD cyclic peptide to targeted αvβ3 on angiogenesis and Irisin to be transported and delivered in adipose tissue based on the local pH value. This project is also to develop a one-stop MR evaluation system to noninvasively monitor the lipid content in white and brown adipose tissue, the adipose tissue angiogenesis and browning of white adipose tissue in the structural, functional and molecular level in a mouse model after high fat diet at 7.0T micro-MR scanner and near infrared scanner. All the changes and relations will be evaluated in vivo, which will provide evidences for future clinical studies.

激活白色脂肪棕色化在防治肥胖及相关代谢性疾病中起重要作用。脂肪组织血管新生与白色脂肪棕色化密切相关，肌肉组织分泌的多肽类激素Irisin通过血液循环到达脂肪组织诱导白色脂肪棕色化，但是，Irisin、脂肪组织血管新生及白色脂肪棕色化三者间的关系及其作用机制的研究目前尚未有文献报道，迫切需要新颖的分子影像和结构功能成像对上述过程进行活体无创准确评估。本项目拟构建双功能、双模态分子探针靶向脂肪组织新生血管内皮αvβ3整合素受体并利用脂肪组织内弱酸环境下pH控释Irisin，采用超高场7.0T磁共振仪及近红外光学成像仪，从分子水平、脂肪组织脂质含量水平及微循环灌注水平建立一站式活体磁共振/近红外评价体系，探讨Irisin在高脂饮食诱导下脂肪组织血管新生及白色脂肪棕色化过程中的作用及相关机制，为Irisin进一步临床试验提供理论依据。

激活白色脂肪棕色化在防治肥胖及相关代谢性疾病中起重要作用。脂肪组织血管新生与白色脂肪棕色化密切相关，肌肉组织分泌的多肽类激素Irisin通过血液循环到达脂肪组织诱导白色脂肪棕色化。Irisin、脂肪组织血管新生及白色脂肪棕色化三者间的关系及其作用机制如何亟需进一步研究。本项目从细胞及动物层面验证Irisin干预白色脂肪发生棕色化转变。首先成功培养、鉴定原代白色脂肪细胞，并在细胞层面成功显示Irisin导致白色脂肪棕色化，随着干预剂量一定程度的增加，白色脂肪棕色化程度增高，为进一步活体实验奠定基础；为了活体动物实验的可视化及定量化，本项目从多模态影像角度，为白色脂肪棕色化研究提供活体无创影像评价方法，运用棕色脂肪特异性近红外光学分子影像探针（MEH-PPV-COOH30）对白色脂肪棕色化过程进行活体敏感成像，Micro-CT及Micro-MR成像活体动态定量小鼠皮下、内脏及总体白色脂肪体积，无创准确评估Irisin干预组小鼠白色脂肪体积明显下降，并且白色脂肪组织脂质含量减低，离体组织病理学、免疫组织化学化及蛋白表达检测证实白色脂肪细胞体积缩小，并且白色脂肪细胞发生棕色化转变；为了进一步明确白色脂肪棕色化转变和血管新生之间的关系，应用68Ga-RGD-PET/CT靶向评估Irisin与脂肪组织血管新生及白色脂肪棕色化之间关系及相互作用机制，明确Irisin干预后小鼠白色脂肪组织内新生血管增加，两者之间的关系密切。能谱CT扫描通过物质分离技术及动态增强扫描，活体动态准确评估大鼠脂肪组织物质组成及微血管差异。本项目为阐明白色脂肪棕色化及血管新生之间的关系及验证Irisin的临床应用前景提供理论依据，为进一步研究白色脂肪棕色化开辟新的思路。