Greenberg Studies

Role of Regulatory MicroRNAs in Rheumatoid Arthritis

Principal Investigators Jeffrey Greenberg, MD, MPH; Michael Dustin, PhD; Mukundan Attur, PhD; Alexandra Zanin-Zhorov, PhD

Co-investigators: Eva Hernando, PhD; Jose Scher, MD; Steven Abramson, MD

MicroRNAs (MiRNAs) regulate the translation and degradation of messenger RNAs (mRNAs), and have been estimated to regulate 30% of all genes. Abnormal expression of miRNA has been observed across a variety of tissue types and diseases, primarily in patients with malignancies. Regulatory T (Treg) cells play a major role in immunological tolerance, and ablation of Treg cells in healthy mice have been observed to provoke autoimmune disease. Disruption of dicer, a key enzyme in miRNA processing and generation, has been observed to reduce the frequency of Treg cells. Additionally, it has been shown that ablation of dicer and other selective miRNAs in Treg cells leads to loss of immune suppressive function. For this pilot proposal, we will examine two specific aims relating to the role of miRNAs in rheumatoid arthritis. In the first specific aim, miRNA function will be examined in Treg cells. We hypothesize that expression levels of enzymes involved in miRNA synthesis will be different in Treg cells from RA patients compared to Treg cells purified from healthy donors. The second specific aim will identify differentially expressed miRNAs in RA patients. Specifically, we will test the hypothesis that microRNAs detectable in the peripheral blood and synovium can serve as prognostic biomarkers of disease severity in RA patients. Understanding the contribution of miRNAs to Treg cell function, and the identification of candidate miRNAs that are differentially expressed in severe RA patients, will provide preliminary evidence on the role of microRNAs in RA to support collaborative R01 or program project grants. This collaborative proposal of miRNA expression in RA patients represents a new research direction for both the Greenberg/Attur labs (Rheumatology) and Dustin (Pathology) lab.