Functional Contributions of the Noncoding Genome in Atherosclerosis Risk Factors

PROJECT SUMMARY/ABSTRACT This application describes a five-year plan for my career development to define the contributions of mouse and human noncoding RNAs in cardiometabolic disorders. Sex differences are well-known in cardiometabolic diseases including atherosclerosis. There are significant numbers of long noncoding RNAs (lncRNAs) that have been implicated in executing functions in a highly context-specific manner, but their role in cardiovascular disease remains a work in progress. A major limitation to appreciating the significance of lncRNAs between sexes is the inability to test their function in vivo and having logical paradigms that prioritize lncRNA discovery. Thus, the overarching scientific goal of this application is to examine the contribution of long noncoding RNAs in hepatic lipid metabolism and their potential implications for cardiovascular and metabolic diseases. Leveraging an ambitious in vivo screen, I have prioritized and focused on one lncRNA, Xtendr, that shows lipid sensitive and highly sexually dimorphic effects. My preliminary data suggest that activating this lncRNA affects liver lipid content using the liver specific CRISPR modulation mice. Capitalizing on my preliminary data and the cutting- edge CRISPR activation and inhibition mouse models, I will test the influence and mechanism of Xtendr on hepatic lipid homeostasis and sex-specific hepatic traits (Aim 1). In Aim 2, I will capitalize on an advanced humanized liver mouse model that will be applied to interrogate the functional conservation of mouse lncRNAs with their syntenic human orthologs. Collectively, this project will reveal the importance of uncharacterized lncRNAs in sex dimorphic hepatic lipid metabolism within an in vivo system and uncover the challenging question about the complex relationships between sequence, synteny, and functional conservation.