HL-Regulation of Angiogenesis in the Obese Adipose Tissue by Secreted microRNAs

项目摘要 HL-142：肥胖及其伴随的代谢紊乱代表着巨大的公共健康 是我们这个时代的挑战，被认为是心血管疾病的独立危险因素 （CVD）。脂肪组织（AT）扩张和重塑是一个持续的过程， 在肥胖状态下改变，其特征在于增加的促炎状态， 血管生成反应和纤维化。虽然脂肪细胞是协调局部变化的关键参与者 在微环境中，许多证据也指出巨噬细胞在 这种重塑事件通过影响脂肪细胞和内皮细胞（EC）的血管生成， 功能协调发展的由于血管生成是AT重塑的限速步骤，因此， 了解巨噬细胞和内皮细胞之间的相互作用。人们普遍认为，肥胖是 伴随着巨噬细胞组成的变化，从抗炎和 血管生成形式，高度炎症形式负责产生的负面结果， 从肥胖。转录后调控网络的重要参与者是小的非- 编码RNA，microRNA（miRNAs），其在控制 MΦ的转录网络。有趣的是，miRNAs可以在细胞间转移， 外泌体，从而促进细胞之间的信息交换。分子组成 并且外泌体的含量可以根据分泌是组成性的还是非组成性的而变化。 细胞活化的结果。我们假设在肥胖AT中，激活的巨噬细胞产生 外泌体含有一组特定的miRNA，靶向EC调节其功能， 控制基因表达，从而影响AT扩张和重塑。该项目将： 回答有关外泌体特异性和功能的重要问题;提供关键见解 巨噬细胞来源的microRNA作为旁分泌通讯的载体 巨噬细胞与内皮细胞在AT血管生成调控中的作用。这些发现将为 识别调节AT扩张的创新治疗策略的方法， 肥胖时的重塑

PROJECT SUMMARY HL-142: Obesity and its accompanying metabolic disorders represent the great public health challenge of our time and is considered an independent risk factor for cardiovascular disease (CVD). Adipose tissue (AT) expansion and remodeling is an ongoing process that is pathologically altered in the obese state, which is characterized by increased pro-inflammatory state, inadequate angiogenic response and fibrosis. Although adipocytes are key players orchestrating local changes in the microenvironment, much evidence also points towards a pivotal role for macrophages in such remodeling events, by affecting both adipocyte and endothelial cell (EC) angiogenic functions. Because angiogenesis is a rate-limiting step for AT remodeling, it is essential to understand the crosstalk between macrophages and ECs. It is accepted that obesity is accompanied by a change in the composition of macrophages, from an anti-inflammatory and angiogenic form, to a highly inflammatory form responsible for the negative outcomes that arise from obesity. Important players of the post-transcriptional regulatory network are the small non- coding RNAs, microRNAs (miRNAs), which have a demonstrated role in the control of transcriptional networks in MΦs. Intriguingly, miRNAs can be transferred from cell to cell by exosomes, thus facilitating the exchange of information among cells. The molecular composition and content of exosomes may vary depending on whether the secretion is constitutive or a consequence of cell activation. We hypothesize that in obese AT, activated macrophages produce exosomes that contain a specific set of miRNAs that target ECs modulating their function, by controlling gene expression and therefore affecting AT expansion and remodeling. This project will: answer important questions regarding exosome specificity and function; provide critical insights into the contribution of macrophage-derived microRNAs as vehicles of paracrine communication between macrophage and ECs in the regulation angiogenesis in the AT. These findings will pave the way to the identification of innovative therapeutic strategies to modulate AT expansion and remodeling during obesity.