Post-Transcriptional Control of Aging-Associated Inflammation and Bone Homeostasis

衰老相关炎症和骨稳态的转录后控制

• 批准号: 10155463
• 负责人: Keith L Kirkwood
• 金额: $ 37.88万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-07 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10155463
• 关键词: 3' Untranslated Regions; Affect; Age; Aging; Alveolar; Alveolar Bone Loss; Anti-Inflammatory Agents; Binding; Blood; Bone Marrow; Bone remodeling; Cell Differentiation process; Cells; Chronic; Coin; Data; Disease Progression; Elderly; Elements; Failure; Family; Functional disorder; Future; Gene Delivery; Health; Homeostasis; Human; Immune; Immune system; Impairment; Incidence; Individual; Inflammaging; Inflammation; Inflammatory; Inflammatory Response; Interleukin-6; Intrinsic factor; Knock-in Mouse; Knockout Mice; Link; Lymphocyte; Maintenance; Matrix Metalloproteinases; Messenger RNA; Metabolism; Molecular; Mus; Myelogenous; Myeloid Cells; Myeloid-derived suppressor cells; Nuclear Translocation; Oral; Osteoclasts; PTGS2 gene; Pathogenicity; Performance; Periodontal Diseases; Periodontitis; Phenotype; Population; Post-Transcriptional Regulation; Process; Production; Proteins; Publishing; RNA-Binding Proteins; Regulation; Research Personnel; Resolution; Role; Skeletal bone; Stream; TIS11 protein; TNF gene; Testing; Therapeutic; Tissues; Untranslated Regions; adaptive immunity; adenylate; age related; alveolar bone; bone; bone aging; bone loss; chronic inflammatory disease; cytokine; density; gain of function; healing; healthy aging; insight; long bone; mRNA Stability; macrophage; middle age; oral microbiome; oral pathogen; osteoclastogenesis; prevent; prototype; recruit; sex; skeletal; skeletal tissue; small molecule; therapeutic target; uridylate; young adult

ABSTRACT With advancing age, the immune system undergoes dynamic changes characterized by both impairment of adaptive immunity and activation of low-grade chronic inflammation. This chronic activation of inflammation associated with aging or `inflammaging'. Tristetraprolin (TTP) is an RNA binding proteins that post-translationally bind to adenylate-uridylate–rich elements in the 3′-UTR of target mRNAs (including key pro-inflammatory mRNAs e.g. TNFα, COX-2 and IL-6) to promote their rapid turnover. Importantly, we have recently demonstrated that failure to regulate expression of cytokines at the posttranscriptional level contributes to chronic inflammation and spontaneous alveolar bone loss with age in TTP-/- mice compared to age/sex match controls. Thus, TTP expression appears to be essential for alveolar bone homeostasis in an age-dependent manner. Our preliminary data in this application and recently published data strongly support the concept that macrophages and myeloid- derived suppressor cell (MDSC) populations are expanded with age in TTP-/- mice, with concomitant reduction in lymphocyte populations. Taken together, our results support that notion that TTP may be a critical intrinsic factor of inflammaging and myeloid lineage expansion/differentiation that contributes towards skeletal homeostasis. We propose to test the hypothesis that TTP controls inflammaging and impacts alveolar bone and long bone skeletal health with age. The specific aims of the proposal are: 1) define the role of myeloid-derived TTP on bone homeostasis with age; 2) determine the mechanisms that TTP uses to alter osteoclastogenesis with age; and 3) Establish if increased TTP expression alters bone remodeling during healthy aging. At the conclusion of these studies, new insights regarding TTP will be provided for future studies where would be potentially a therapeutic target for healthy aging of the oral and non-oral skeletal tissues.

摘要 随着年龄的增长，免疫系统经历了动态变化，其特征在于免疫功能的损害， 获得性免疫和低度慢性炎症的激活。这种炎症的慢性激活 与衰老或“炎症”有关。Tristetraprolin（TTP）是一种RNA结合蛋白， 与靶mRNA（包括关键的促炎mRNA）的3′-UTR中富含腺苷酸-尿苷酸的元件结合 例如TNFα、考克斯-2和IL-6）促进其快速周转。重要的是，我们最近证明， 不能在转录后水平调节细胞因子的表达导致慢性炎症， 与年龄/性别匹配对照相比，TTP-/-小鼠随年龄的自发牙槽骨丢失。因此，TTP 其表达似乎以年龄依赖性方式对牙槽骨稳态是必需的。我们的初步 本申请中的数据和最近公布的数据强烈支持巨噬细胞和骨髓- 衍生的抑制细胞（MDSC）群体在TTP-/-小鼠中随着年龄的增长而扩增，伴随着减少。 在淋巴细胞群体中。综上所述，我们的研究结果支持了TTP可能是一个关键的内在因素的观点。 炎症因子和髓系扩增/分化，有助于骨骼 体内平衡我们建议检验TTP控制炎症并影响牙槽骨的假设， 长骨骨骼健康随着年龄的增长。该提案的具体目的是：1）明确骨髓来源的作用 TTP对骨稳态随年龄变化的影响; 2）确定TTP用于改变破骨细胞生成的机制 3）确定TTP表达增加是否改变健康衰老期间的骨重塑。在 这些研究的结论，关于TTP的新见解将提供未来的研究， 可能是口腔和非口腔骨骼组织健康老化的治疗靶点。