RNA深度测序和功能基因组学的研究在人类基因组注释了远远超过蛋白编码基因数量的非编码RNA基因。但是，已知功能的长非编码RNA不多，特别是调控细胞代谢的长非编码RNA研究很少。项目申请人团队鉴定了一个骨骼肌特异表达的Linc-RAM在不同代谢类型的骨骼肌组织表达水平不同，提示Linc-RAM参与调控骨骼肌代谢，Linc-RAM基因敲除小鼠显著抵抗高脂饮食诱导的肥胖。本项目的核心科学问题是探讨Linc-RAM如何调控骨骼肌代谢？Linc-RAM介导的骨骼肌代谢又是如何调控整个机体的代谢稳态平衡？主要研究内容是通过系统鉴定Linc-RAM结合蛋白，特别是与Linc-RAM相互作用的代谢酶，阐明Linc-RAM调控骨骼肌代谢的分子机制；通过系统鉴定Linc-RAM介导的骨骼肌代谢调控的骨骼肌分泌因子进一步揭示Linc-RAM调控骨骼肌与脂肪组织互作维持机体代谢稳态平衡的分子机制。

RNA deep sequencing and functional genomics analysis demonstrate significant number of noncoding RNAs encoded in the genome of human and other model organism. Although increasing lines of evidence show that lncRNA have profound functions in regulating various aspect of cellular biology, development and disease, only a few number of lncRNAs are functionally investigated in detail. In particular, we have known little about the functions of lncRNAs in regulating cell metabolism. We have previously identified a MyoD-regulated skeletal muscle specifically expressed Linc-RAM which significantly enhance myogenic lineage differentiation by interacting with MyoD. Interestingly, we recently found that the functions of Linc-RAM are not limited to myogenic differentiation. Linc-RAM is highly expressed in fully differentiated myotubes and mature myofibers. Furthermore, Linc-RAM preferentially expressed in glycolytic muscle compared to oxidative muscle, suggesting that Linc-RAM implicates in muscle metabolism regulation. Remarkably, we observed that Linc-RAM knockout mice significantly resist high-fat-diet (HFD) induced obesity and improve HFD-induced glucose intolerance and insulin resistance, indicating that skeletal muscle expressed Linc-RAM mediate whole body metabolic homeostasis. Therefore, the observations raise a very interesting scientific question that how does Linc-RAM regulate muscle metabolism? How does Linc-RAM-mediated muscle metabolism orchestrate adipose tissue metabolism and whole body metabolic homeostasis. Here, we proposed a research plan: 1) to investigate the molecular mechanism underlining Linc-RAM-mediated muscle metabolism by systematically identifying Linc-RAM binding proteins (LrBPs) in cytoplasm. Specifically, we will focus on the LrBPs which are metabolic enzymes in regulating muscle metabolism. It is great interest to examine whether the interaction between Linc-RAM and the LrBP affects the enzymatic activity or enzymatic specificity. 2) to elucidate the molecular mechanism underlining Linc-RAM-mediated whole body metabolic homeostasis by identifying Linc-RAM-regulated muscle-secreted factors (Myokines or Myometabolites). The completion of the project will provide fundamental information for the physiological function and molecular mechanism of lncRNAs in regulating cell metabolism and whole body metabolic homeostasis. The findings from this project will definitely benefit to clinical settings implicating metabolic syndrome.