Medical Research

Vanderbilt University Medical Center

Kasey Vickers, MacRae Linton, Ryan Allen, Quanhu Sheng
Nashville, TN
$1,000,000
June 2019

As the leading cause of death worldwide, cardiovascular disease (CVD) affects one in three people.  For decades, plasma cholesterol levels have been considered the leading risk factor for CVD, with low density lipoprotein-cholesterol (LDL-C) as the primary prevention target.  But cholesterol is only part of the equation, as millions of individuals with clinically normal cholesterol levels, managed by statins, still have risk for CVD.  This residual risk is likely conferred by vascular inflammation, which prompts a crucial question: what are the pro inflammatory stimuli that drive the development of atherosclerosis?  Cholesterol is the best known cargo carried by circulating lipoproteins; however, researchers at Vanderbilt University Medical Center discovered that lipoproteins also transport small non-coding RNAs (sRNAs).  Strikingly, the majority of sRNAs on lipoproteins are not human, but microbial, and originate from the host microbiome, diet or other environmental exposure to micro-organisms.  The biological function of microbial sRNAs on lipoproteins is completely unknown.  Could sRNAs be the previously unidentified inflammatory stimuli of atherosclerosis?  Vanderbilt University Medical Center Investigators hypothesize that this previously unmeasurable cargo trafficked on LDL particles engages pro-inflammatory gene regulatory networks to drive atherosclerosis and other metabolic diseases with underlying inflammation.  To test this hypothesis, the researchers will determine how lipoproteins acquire microbial sRNAs, define the biological relevance of microbial sRNAs on lipoproteins, and determine the underlying mechanisms of lipoprotein-mediated cross-kingdom gene regulation.  The discoveries could redefine and disrupt long-held paradigms linking dyslipidemia and inflammation and establish a new field of study for lipoprotein function and extracellular RNA applicable to many chronic diseases.

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