Metabolic disturbances such as dyslipidemia, diabetes and obesity are associated with a number of comorbid conditions including devastating forms of cardiovascular disease. Recently, the discovery of an attractive group of molecules known as long noncoding RNAs (lncRNAs) has introduced a new ?catalog? of diagnostic and therapeutic opportunities for cardiovascular risk mitigation. LncRNAs participate in diverse biologic processes but their involvement to cardiometabolic disease is less well explored. The objective of this project is to define the contributions and mechanisms of action of lncRNAs in adipose tissue formation and function. Capitalizing on our recent discovery of lncRNAs acting as responders to dietary cues and modulators of physiologic pathways with links to common diseases, we hypothesize that transcriptional regulation by long non-coding RNAs in white adipocyte tissue is essential for normal adipose tissue development. Reinforcing this premise our studies show that loss of the lncRNA LeXis is associated with failure to suppress de novo cholesterogenesis in adipocyte precursors and resistance to diet induced obesity.
In aim1, we use a series of molecular, cell biological, and novel animal models to extend our preliminary observations and test out hypothesis defining the function of lncRNAs in adipose tissue.
In aim2, we leverage recent technical advances interrogating the interplay between transcription factors and chromatin to investigate new mechanisms involved in metabolic control and spatial activation patterns of master adipogenic transcription factors. Our studies are expected to shed fundamental insights into mechanisms orchestrating adiposity and may offer new frontiers for drug development targeting obesity and metabolic traits.
Cardiovascular disease (CVD) is leading cause of death in both men and women claiming approximately 18 million lives annually. The disturbing surge in metabolic disorders including obesity, diabetes and dyslipidemia will ensure that CVD will not just fade way. Our proposed studies will provide important insights as to how obesity and cardiovascular disease develop as well as offer novel diagnostic and therapeutic strategies.
|Zhang, Zhengyi; Salisbury, David; Sallam, Tamer (2018) Long Noncoding RNAs in Atherosclerosis: JACC Review Topic of the Week. J Am Coll Cardiol 72:2380-2390|