This proposal describes a five-year mentored physician-scientist training program to define the contribution of long non-coding RNAs in cardiovascular disease. Disturbances in cholesterol homeostasis are major contributors to cardiovascular disease and associated comorbidities. The liver X receptors (LXRs) is central regulators of sterol homeostasis. Activation of LXRs promotes reverse cholesterol transport/excretion and limits cholesterol uptake/absorption. The administration of LXR agonists has potent atheroprotective effects and reverses established disease; hence LXR agonists have generated strong interest as therapeutic targets. The actions of LXRs are opposed by Sterol Regulatory Element-binding Protein 2 (SREBP-2), the master regulator of cholesterol biosynthesis. Although prior studies have implicated microRNAs in lipoprotein metabolism, the contribution of other non-coding RNAs to lipid homeostasis and atherosclerosis remain unexplored. A unique group of non-coding RNAs known as large intergenic non-coding (linc) RNAs exhibit moderate evolutionary conservation and participate in diverse biologic processes with direct links to human diseases. Utilizing next-generation sequencing technology we identified a lincRNA that we named LeXis (Liver-expressed LXR-induced sequence) as a novel LXR target gene. The objective of this project is to define the function of LeXis in physiology and metabolism. My preliminary studies suggest that LeXis regulates serum cholesterol levels in vivo via feedback repression of SREBP-2 and cholesterol biosynthesis. I hypothesize that LeXis plays a role in cholesterol homeostasis through tissue-specific modulation of SREBP-2 transcription. I propose a series of molecular, cell biological, and animal studies to extend my preliminary observations and test my hypothesis. Targeting SREBP-2 in a context-specific manner may lower serum cholesterol while minimizing off target effects. Not only will our proposed work provide fundamental insights into how lncRNAs work, but may also open a new frontier for drug development, since it is conceivable that LeXis mimetic oligonucleotides might be used as therapeutic drugs. Thus, the proposed work is of high translational potential. The outlined program will allow the candidate to develop the skills and tools needed to embark upon this research project, while having the necessary mentorship and support needed towards the goal of maturing into an independent investigator.
The aims of this project are aligned with the major strategic goal of NHLBI to improve our understanding of the molecular and physiologic basis of health and disease.

Public Health Relevance

Metabolic derangement and atherosclerosis are at the epicenter of the most devastating forms of cardiovascular disease. At the interface of cutting edge biology and common cardiovascular problems, we seek to uncover the contributions of long non-coding RNAs to cholesterol regulation and atherosclerosis development. Our preliminary data suggests that non-coding RNAs are induced with high fat diet and regulate serum cholesterol in vivo, thus our work may result in targeted diagnostic and therapeutic strategies that mitigate the overwhelming impact of metabolic disturbance on cardiovascular disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL128822-04
Application #
9503755
Study Section
NHLBI Mentored Clinical and Basic Science Review Committee (MCBS)
Program Officer
Huang, Li-Shin
Project Start
2015-07-10
Project End
2020-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Tarling, Elizabeth J; Clifford, Bethan L; Cheng, Joan et al. (2017) RNA-binding protein ZFP36L1 maintains posttranscriptional regulation of bile acid metabolism. J Clin Invest 127:3741-3754
Tontonoz, Peter; Wu, Xiaohui; Jones, Marius et al. (2017) Long Noncoding RNA Facilitated Gene Therapy Reduces Atherosclerosis in a Murine Model of Familial Hypercholesterolemia. Circulation 136:776-778
Sallam, Tamer; Jones, Marius C; Gilliland, Thomas et al. (2016) Feedback modulation of cholesterol metabolism by the lipid-responsive non-coding RNA LeXis. Nature 534:124-8