Micro RNAs and chronic, low-grade inflammation

 描述（由申请人提供）：慢性、低度炎症是大多数与年龄相关的人类疾病的促成因素。然而，在衰老期间维持慢性炎症反应的分子机制仍然知之甚少，使得难以治疗这种有害的病症。在过去的几年里，研究表明，哺乳动物非编码microRNAs（miRNAs）调节各种急性炎症反应在年轻的小鼠。我们推测，miRNAs在衡量衰老过程中的炎症方面也起着关键作用。与此相一致，最近已显示去除miR-146 a会导致年龄依赖性炎症性疾病，该疾病重演了患者慢性炎症的许多方面，包括进展为缩短寿命的疾病，如癌症。我们使用miR-146 a-/-模型来鉴定和研究促进年龄相关炎症的其他miRNA，并确定miR-155是miR-146 a-/-小鼠模型中出现疾病所必需的。我们还发现，miR-155是中年miR-146 a-/-小鼠中T滤泡辅助细胞自发积累、自身抗体产生和随后出现的组织炎症所必需的。此外，我们也有初步数据表明miR-155的T细胞内在作用，因为它促进miR-146 a-/-小鼠的慢性炎症。我们将开展一项研究计划，以确定miR-146 a-/-中哪些下游表型依赖于T细胞中miR-155的功能，并确定Tfh细胞的具体贡献。还将研究miR-155指导miR-146 a-/-小鼠中Tfh细胞发育的分子机制。此外，我们将把我们的研究扩展到临床，并确定miR-155和Tfh细胞水平是否与“健康”中年患者的慢性低度炎症的其他标志物相关。总之，我们的研究计划将为慢性炎症的潜在机制提供有价值的见解，并确定miR-155和Tfh细胞是否是有希望的治疗靶点，有可能减少慢性，低度炎症和源于这种病理状态的无数疾病。

 DESCRIPTION (provided by applicant): 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.