More than one-third of U.S. adults are obese, which predisposes many people to an increased risk of type 2 diabetes and cardiovascular disease. Endothelial dysfunction is an early and prominent feature in obesity and a critical step in the initiation and progression of atherosclerosis, a pathological condition resulting in coronary artery disease. While progress has been made in treating atherosclerosis by use of statins, treatments have not addressed the residual risk of cardiovascular disease. To develop better treatments, there is a need to elucidate the underlying mechanisms of obesity-associated endothelial dysfunction that contribute to increased risk for obesity-related atherosclerosis. Changes in the expression and function of long non-coding RNAs (lncRNAs) ? a class of RNA transcripts that regulate gene expression in a range of signaling pathways ? contribute to the pathogenesis of obesity-related diseases via various mechanisms. However, lncRNA-mediated cellular, molecular, and epigenetic mechanisms underlying endothelial dysfunction in obesity and obesity-associated cardiovascular disease remain largely unknown. A preliminary transcriptome analysis of mouse vascular endothelium using RNA-sequencing identified many lncRNAs with significant changes in expression following metabolic stress. Among these lncRNAs, maternally expressed gene 3 (Meg3) is conserved between mice and humans and has shown particular promise in playing an essential role in the mechanisms underlying endothelial dysfunction and atherosclerosis. However, exactly how Meg3 affects endothelial function and atherosclerosis is unknown. To address these gaps in knowledge, this project will test a central hypothesis ? that lncRNA Meg3 can inhibit the development of atherosclerosis by protecting endothelial function in response to metabolic stress ? using two specific aims (SAs): SA1) identify the mechanism by which Meg3 regulates endothelial function and SA2) determine whether Meg3 knockdown accelerates atherosclerosis and its related mechanisms. In SA1, an array of methods will be used to determine: 1) the signaling pathway and cis- and trans-factor(s) that mediate the induction of Meg3 in response to metabolic stress and DNA damage-inducing stimuli and 2) the role of Meg3 in regulating p53 signaling and endothelial function. In SA2, a low-density lipoprotein receptor knockout mouse model of atherosclerosis will be used to examine the effects of altering Meg3 expression on p53 signaling and endothelial function in vivo, including the formation of atherosclerotic plaques. This research will contribute fundamental knowledge about the role of lncRNA Meg3 in obesity-associated endothelial dysfunction and atherosclerosis and will contribute to Dr. Sun's long-term goal to inform the development of better strategies to attenuate the development of atherosclerosis by targeting metabolic stress-induced endothelial dysfunction in obesity. In future work the dietary regulators of Meg 3 will contribute to the Nebraska Center for the Prevention of Obesity through Dietary Molecules (NPOD)'s thematic focus of identifying biological, primarily food-borne signals that prevent, treat, and cure obesity and obesity-related diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory Grants (P20)
Project #
2P20GM104320-06
Application #
9795741
Study Section
Special Emphasis Panel (ZGM1)
Project Start
Project End
Budget Start
2019-06-01
Budget End
2020-05-31
Support Year
6
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Nebraska Lincoln
Department
Type
DUNS #
555456995
City
Lincoln
State
NE
Country
United States
Zip Code
68503
Hakguder, Zeynep; Shu, Jiang; Liao, Chunxiao et al. (2018) Genome-scale MicroRNA target prediction through clustering with Dirichlet process mixture model. BMC Genomics 19:658
McAtee, Caitlin O; Booth, Christine; Elowsky, Christian et al. (2018) Prostate tumor cell exosomes containing hyaluronidase Hyal1 stimulate prostate stromal cell motility by engagement of FAK-mediated integrin signaling. Matrix Biol :
Manca, Sonia; Upadhyaya, Bijaya; Mutai, Ezra et al. (2018) Milk exosomes are bioavailable and distinct microRNA cargos have unique tissue distribution patterns. Sci Rep 8:11321
E Silva, Bruno Vieira Resende; Rad, Milad Ghiasi; Cui, Juan et al. (2018) A Mobile-Based Diet Monitoring System for Obesity Management. J Health Med Inform 9:
Fan, Rong; Toney, Ashley Mulcahy; Jang, Yura et al. (2018) Maternal n-3 PUFA supplementation promotes fetal brown adipose tissue development through epigenetic modifications in C57BL/6 mice. Biochim Biophys Acta Mol Cell Biol Lipids 1863:1488-1497
Nordgren, Tara M; Heires, Art J; Zempleni, Janos et al. (2018) Bovine milk-derived extracellular vesicles enhance inflammation and promote M1 polarization following agricultural dust exposure in mice. J Nutr Biochem 64:110-120
Martínez, Inés; Maldonado-Gomez, Maria X; Gomes-Neto, João Carlos et al. (2018) Experimental evaluation of the importance of colonization history in early-life gut microbiota assembly. Elife 7:
Zhang, Hanyuan; Vieira Resende E Silva, Bruno; Cui, Juan (2018) miRDis: a Web tool for endogenous and exogenous microRNA discovery based on deep-sequencing data analysis. Brief Bioinform 19:415-424
Leiferman, Amy; Shu, Jiang; Grove, Ryan et al. (2018) A diet defined by its content of bovine milk exosomes and their RNA cargos has moderate effects on gene expression, amino acid profiles and grip strength in skeletal muscle in C57BL/6 mice. J Nutr Biochem 59:123-128
Okla, Meshail; Zaher, Walid; Alfayez, Musaad et al. (2018) Inhibitory Effects of Toll-Like Receptor 4, NLRP3 Inflammasome, and Interleukin-1? on White Adipocyte Browning. Inflammation 41:626-642

Showing the most recent 10 out of 68 publications