Role of microRNAs in synovial fibroblast biology and functions

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Background/Rationale: Synovial fibroblasts are predominant cells present in the synovial membrane and are crucial for the maintenance of joint homeostasis by contributing towards the production of extracellular matrix (ECM). Synovial fibroblasts in response to specific stimuli (cytokines and growth factors) acquire myofibroblast-type phenotype and produce excessive amount of ECM resulting in tissue fibrosis and loss of function. The endogenous mediators that control synovial fibroblast functions (differentiation, migration, proliferation and adhesion) and ECM production are largely unknown. MicroRNAs (miRNAs) are small non-coding RNAs that regulate more than 60% of all coding genes and play pivotal roles in various pathophysiological processes. The exact role of microRNAs in synovial fibroblast biology and functions is largely unknown.******Preliminary Studies: Our recent studied have identified a panel of microRNAs (miR-23a-3p, 24-3p, 27a-3p, 27b-3p, 29c-3p, 186-5p and 378a-5p) that are highly abundant in normal human synovium, especially synovial fibroblasts and their expression is dramatically elevated in response to inflammatory stimuli, IL-1. The specific roles of these identified miRNAs in synovial biology and its functions has never been reported. Our preliminary data shows that, in response to inflammatory IL-1 stimulation (and not TNF- or IL-6), all these miRNAs show significant elevation in their expression. Our pilot data on miR-27b-3p strongly suggest that miR-27b-3p is activated by IL-1 and is involved in fibroblast-myofibroblast differentiation and ECM production. We anticipate that other identified miRNAs may also play a role in certain synovial fibroblast functions associated with ECM production.******Hypothesis: miRNAs may play a central role in controlling the ECM production by inducing the differentiation of synovial fibroblast to myofibroblast-like cells as well as in synovial fibroblast migration, proliferation and adhesive signaling in the synovium.******To examine the exact role(s) of miRNAs in ECM production, the major objectives of this program are: ***1. Determine the role of identified microRNAs in synovial fibroblast differentiation (fibroblast-myofibroblast like cells), proliferation and survival. ***2. Determine the role of identified microRNAs in synovial fibroblast migration, adhesive signaling, ECM contraction and its production.***3. Identify the signaling pathways through which these miRNAs operate in synovial fibroblasts to mediate ECM production.******Significance: This research program will enable significant advancement in the field of synovial fibroblast biology and help identify crucial endogenous mechanisms that control synovial fibroblast-myofibroblast differentiation, migration, adhesion and ECM production. This program will also provide world-class training to create highly skilled and qualified research personnel.********