Chronic, low-grade inflammation is a contributing factor to most age-related human diseases. However, the molecular mechanisms that sustain chronic inflammatory responses during aging remain poorly understood making it difficult to treat this deleterious condition. Over the past few years, studies have indicated that mammalian noncoding microRNAs (miRNAs) regulate a variety of acute inflammatory responses in young mice. We hypothesize that miRNAs also play critical roles in gauging inflammation during the aging process. Consistent with this, removal of miR-146a has recently been shown to cause an age-dependent inflammatory disease that recapitulates many aspects of chronic inflammation in patients, including progression to life-shortening disorders like cancer. We have used the miR-146a-/- model to identify and study other miRNAs that promote age-related inflammation, and have determined that miR-155 is necessary for disease to emerge in the miR-146a-/- mouse model. We have also found that miR-155 is required for spontaneous accumulation of T follicular helper cells, autoantibody production and the subsequent tissue inflammation that emerges in middle-aged miR-146a-/- mice. Further, we also have preliminary data indicating a T cell-intrinsic role for miR-155 as it promotes chronic inflammation in miR-146a-/- mice. We will carry out a research plan to determine which downstream phenotypes in miR-146a-/- are dependent on miR-155 function in T cells, and also determine the specific contribution by Tfh cells. The molecular mechanism by which miR-155 instructs Tfh cell development in miR-146a-/- mice will also be investigated. Furthermore, we will extend our studies into the clinic and determine if miR-155 and Tfh cell levels correlate with other markers of chronic, low-grade inflammation in healthy middle aged patients. Taken together, our research plan will provide valuable insight into the mechanisms underlying chronic inflammation, and determine whether miR-155 and Tfh cells are promising therapeutic targets with the potential to reduce chronic, low-grade inflammation and the myriad of diseases that stem from this pathological condition.
Chronic, low-grade inflammation is a contributing factor to most diseases associated with aging. However, the molecular and cellular mechanisms that regulate chronic inflammation are still being deciphered. We will determine how specific regulatory microRNAs function to control age-dependent inflammatory status, and our work will identify novel therapeutic targets to treat this harmful condition.
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