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：
10405077
负责人：
Keith L Kirkwood
金额：
$ 37.5万
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 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10405077
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 Persons 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，免疫系统经历动态变化，其特征是低度慢性炎症的适应性免疫学和激活。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，后翻译后与靶mRNA的3'-UTR（包括关键的促炎性mRNA）结合到腺苷酸 - 尿酸 - 富元素元素例如TNFα，COX-2和IL-6）以促进其快速离职。重要的是，我们最近证明了未能调节在转录后水平上细胞因子的表达会导致慢性感染和与年龄/性别匹配对照相比，TTP - / - 小鼠的赞助牙槽骨损失随着年龄的增长而流失。那，ttp 表达似乎对肺泡骨稳态以年龄的依赖方式至关重要。我们的初步该应用程序中的数据和最近发布的数据强烈支持巨噬细胞和髓样的概念衍生抑制细胞（MDSC）种群随着TTP - / - 小鼠的年龄而扩大，并同时还原在淋巴细胞种群中。综上所述，我们的结果支持认为TTP可能是关键的内在观念炎症和髓样谱系扩张/分化的因素，有助于骨骼稳态。我们建议测试TTP控制炎症并影响肺泡骨和长骨骨骼健康随着年龄的增长。该提案的具体目的是：1）定义髓样衍生的作用随着年龄的增长，骨骼体内平衡的TTP； 2）确定TTP用来改变破骨细胞发生的机制随着年龄的增长； 3）确定TTP表达增加是否会在健康衰老过程中改变骨重塑。在结论这些研究，将为将来的研究提供有关TTP的新见解可能是口腔和非口腔骨骼组织健康衰老的治疗靶标。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Tristetraprolin limits age-related expansion of myeloid-derived suppressor cells.

DOI：
10.3389/fimmu.2022.1002163
发表时间：
2022
期刊：
FRONTIERS IN IMMUNOLOGY
影响因子：
7.3
作者：
Kwack, Kyu Hwan;Zhang, Lixia;Kramer, Elliot D.;Thiyagarajan, Ramkumar;Lamb, Natalie A.;Arao, Yukitomo;Bard, Jonathan E.;Seldeen, Kenneth L.;Troen, Bruce R.;Blackshear, Perry J.;Abrams, Scott I.;Kirkwood, Keith L.
通讯作者：
Kirkwood, Keith L.

Myeloid-derived suppressor cells in obesity-associated periodontal disease: A conceptual model.