Rheumatoid arthritis (RA) is an inflammatory autoimmune disease associated with a two-fold increased cardiovascular risk independent of lipoprotein concentrations and other traditional risk factors. Several lines of evidence suggest that impaired high-density lipoprotein (HDL) function rather than altered concentrations contributes to increased cardiovascular risk; in RA high HDL cholesterol is associated paradoxically with increased cardiovascular risk in the setting of high inflammation or oxidative stress. Mechanisms underlying impaired HDL function are unclear, but a recent discovery that HDL transports microRNAs (miRNAs) between cells provides a novel mechanism by which HDL can regulate intercellular communication in a highly specific manner. miRNAs are small non-coding RNAs that are powerful gene regulators of immunity and inflammation. For example, we found that HDL transports miRNAs to endothelial cells altering adhesion molecule expression. Nothing is known about miRNA cargo of HDL in RA, a potential mechanism whereby inflammation at one site may have distant deleterious effects. The overarching hypothesis is that in RA an altered HDL-miRNA cargo is delivered to cells key to the development of atherosclerosis leading to altered cellular responses providing a mechanism for increased CV risk in patients with RA. Building on preliminary data, Aim 1 will further define HDL-miRNA cargo in RA by sequencing small RNAs from purified HDL from patients with RA and controls. These findings will help select those HDL-miRNAs most closely associated with inflammation and endothelial function in RA.
In Aim 2, macrophages will be treated with RA and control HDL. The differential miRNA transfer and resultant change in pro-inflammatory cytokine expression will be quantified.
In Aim 3, endothelial cells will be treated with RA and control HDL. The differential miRNA transfer and resultant change in adhesion molecule expression and nitric oxide production will be quantified. This novel mechanism of intercellular communication by HDL-miRNA delivery will offer new avenues of therapeutics for RA to decrease cardiovascular risk. The applicant, Dr. Ormseth, has a strong background in clinical and translational research and is committed to an academic career in rheumatology. Following her clinical rheumatology fellowship at Vanderbilt, she obtained a Master of Science in Clinical Investigation degree and completed an additional two year research fellowship, funded by a T-32 grant. Her career goal is to become an independent investigator in the area of lipid and miRNA biology pertaining to mechanisms and treatment of accelerated atherosclerosis in patients with inflammatory rheumatic diseases. Additional mentored research time and training in topics such as systems biology and lipoprotein metabolism will help expand her laboratory and bioinformatics skills relevant to her career path. Vanderbilt University provides an exceptional environment in which to develop. Highlights are the Newman Society, which seeks to equip young investigators for independence, core facilities like VANTAGE with state- of-the-art RNAseq technology, and the deep commitment of the University to support young investigators. The Department of Medicine and Division of Rheumatology support Dr. Ormseth's plans. Her mentors, Drs. Stein, Linton, and Vickers, are internationally recognized, have track records of successful mentees, and have the necessary resources to train her and develop her career. Dr. Ormseth's innovative research proposal along with excellent mentoring and an outstanding environment will together help her to be competitive for independent R01 funding.
Accelerated cardiovascular disease is the number one cause of early death in patients with Rheumatoid arthritis (RA), a chronic inflammatory autoimmune disease affecting nearly 1% people in the United States. MicroRNAs are potent regulators of gene expression and play important roles in inflammation and cardiovascular disease; thus, manipulation of microRNAs holds great potential for future therapeutic strategies. This proposal focuses on the role of altered HDL-microRNA cargo delivery to cells of the vasculature as a potential mechanism for increased cardiovascular risk in RA.
