Micro RNAs and chronic, low-grade inflammation

Micro RNA 与慢性、低度炎症

• 批准号: 9065475
• 负责人: Ryan M O'Connell
• 金额: $ 33.53万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-15 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9065475
• 关键词: Acute; Adoptive Transfer; Age; Aging; Aging-Related Process; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Area; Autoantibodies; Autoimmunity; B-Lymphocytes; Biological Assay; Chronic; Clinic; Clinical; Complex; Data; Development; Diagnostic; Disease; Excision; Gene Expression; Gene Targeting; Genetic; Health; Helper-Inducer T-Lymphocyte; Human; Immune; Individual; Inflammation; Inflammatory; Inflammatory Response; Interleukin-6; Investigation; Knowledge; Life; Longevity; Malignant Neoplasms; Messenger RNA; Metabolism; Methods; MicroRNAs; Modeling; Molecular; Mus; NF-kappa B; Older Population; Pathway interactions; Patients; Phenotype; Play; Process; Production; Property; Regulation; Research; Role; Serum; Structure of germinal center of lymph node; Symptoms; T cell response; T-Lymphocyte; Testing; Therapeutic; Time; Tissues; Transcription Factor AP-1; Translating; Work; age related; base; body system; cell growth regulation; disease phenotype; genetic approach; human disease; individual patient; inflammatory marker; insight; middle age; mortality; mouse model; new therapeutic target; novel; novel marker; overexpression; prevent; research study; stem; targeted treatment; therapeutic target; transcription factor

 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.

 描述（由适用提供）：慢性，低度炎症是导致大多数与年龄相关的人类疾病的促成因素。然而，衰老过程中持续慢性炎症反应的分子机制仍然很难理解，因此很难治疗这种有害状况。在过去的几年中，研究表明，哺乳动物非编码的microRNA（miRNA）调节年轻小鼠的各种急性炎症反应。我们假设miRNA在衰老过程中还发挥了关键作用。与此相一致，最近已证明MiR-146a的去除会引起年龄依赖性的炎症性疾病，该疾病概括了患者的慢性感染的许多方面，包括癌症等人生疾病的发展。我们已经使用miR-146a - / - 模型来识别和研究其他促进与年龄相关的炎症的miRNA，并确定miR-155对于疾病在miR-146a - / - 小鼠模型中出现是必要的。我们还发现，T卵泡辅助细胞的赞助积累，自身抗体的产生以及随后在中年miR-146a - / - 小鼠中出现的组织注射所必需的miR-155。此外，我们还拥有初步数据，表明miR-155的T细胞中性作用，因为它促进了miR-146a - / - 小鼠的慢性炎症。我们将执行一个研究计划，以确定miR-146a - / - 中哪些下游表型取决于T细胞中的miR-155功能，并确定TFH细胞的特定贡献。 MiR-155指导MiR-146a - / - 小鼠中TFH细胞发育的分子机制也将进行研究。此外，我们将把研究扩展到诊所，并确定MiR-155和TFH细胞水平是否与“健康”中年患者的慢性低级感染的其他标记相关。综上所述，我们的研究计划将为慢性感染的机制提供宝贵的见解，并确定miR-155和TFH细胞是否有希望的治疗靶标，有可能减少慢性，低度感染和源于这种病理状况的无数疾病。