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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

抽象的随着年龄的增长，免疫系统会发生动态变化，其特征是免疫系统受损适应性免疫和低度慢性炎症的激活。 Tristetraprolin (TTP) 是一种翻译后的 RNA 结合蛋白。与目标 mRNA（包括关键的促炎 mRNA）3′-UTR 中富含腺苷酸-尿苷酸的元件结合重要的是，我们最近证明了这一点。未能在转录后水平调节细胞因子的表达会导致慢性炎症和与年龄/性别匹配的对照组相比，TTP-/- 小鼠随年龄的增长自发性牙槽骨丢失。我们初步认为，这种表达对于牙槽骨稳态至关重要。本申请中的数据和最近发表的数据强烈支持巨噬细胞和骨髓细胞的概念 TTP-/- 小鼠中衍生抑制细胞 (MDSC) 群体随着年龄的增长而扩大，并随之减少总而言之，我们的结果支持 TTP 可能是一个关键的内在因素。炎症和骨髓谱系扩张/分化的因素，有助于骨骼我们建议检验 TTP 控制炎症并影响牙槽骨的假设。长骨骨骼健康随年龄的增长该提案的具体目标是： 1) 明确髓源性的作用。 TTP 对骨稳态随年龄的影响；2) 确定 TTP 用于改变破骨细胞生成的机制随着年龄的增长；3) 确定 TTP 表达的增加是否会改变健康衰老过程中的骨重塑。这些研究的结论将为未来的研究提供关于 TTP 的新见解口腔和非口腔骨骼组织健康老化的潜在治疗靶点。