Functional investigation of lincADAIN in obesity-induced adipose tissue inflammation

Project: Research

Investigators

  • Marcella E OREILLY (PI)

Description

Long intergenic non-coding RNAs (lincRNAs) are important emerging regulators of cellular functions. Dysfunctional adipose tissue (AT), characterized by increased inflammation and insulin resistance, plays a central role in the development of type 2 diabetes (T2DM) and atherosclerotic cardiovascular diseases. Profiling of adipose transcriptome during low-dose experimental endotoxemia in humans (N=25) revealed novel lincRNAs that are modulated in inflamed AT. LincADAIN is a top candidate that is 1) abundantly expressed in adipose and conserved between mouse and human; 2) reduced in both obesity-induced chronic and LPS-induced acute inflammation; 3) Knock down (KD) of lincADAIN increased protein but not mRNA levels of inflammatory cytokines in adipocytes. LincADAIN co-localizes with P-bodies, cytoplasmic ribonucleoprotein granules that are important regulators of mRNA translation. I hypothesize that lincADAIN modulates specific mRNA binding proteins (mRBPs) in P-bodies, regulating P-body mediated translation repression of mRNA in adipocytes. This will be tested through: 1) KD and overexpression (OE) of lincADAIN in human adipocyte stromal cell (ASC) adipocytes LPS in vitro, and 2) extraction and profiling of P-body mRNA (RNA-seq) and protein (Mass Spectrometry) contents under these conditions. 3) Implantation of human adipocytes with KD and OE of lincADAIN into NOD scid gamma mouse (NSG) mice on high fat diet (HFD) or chow. These in vivo studies will test if lincADAIN and P-bodies regulates adipose cytokine production and AT inflammation in obesity. Investigation of lincADAIN may provide novel mechanistic and genomic insights into adipocyte cellular functions in response to diet induced obesity and provide innovative diagnostic and therapeutic opportunities for cardiometabolic disease.
Award amount$128,836.00
Award date01/01/2020
Program typePostdoctoral Fellowship
Award ID20POST35050045
Effective start/end date01/01/202012/31/2021
StatusActive