Repressing Retrotransposon LINE-1: New Concepts for Osteoarthritis Treatment

抑制逆转录转座子 LINE-1：骨关节炎治疗的新概念

基本信息

批准号：
9912431
负责人：
QIAN CHEN
金额：
$ 39.38万
依托单位：
RHODE ISLAND HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-16 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9912431
关键词：
Address Aging Animal Model Antiviral Agents Bioinformatics Bone remodeling Cartilage Cell Aging Cells Chondrocytes Chronic Cytidine Data Degenerative polyarthritis Development Disease Elderly Elements FDA approved Gene Expression Genes Genetic Transcription Goals Health Histology Human Inflammation Injury Intervention Joints Knowledge Lamivudine Lead Length Lesion Mechanics Medial meniscus structure Mission Molecular Morphology Movement Mus Nuclear Nucleosides Outcome Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Phase Phenotype Process Proteins Public Health RNA Repression Research Retrotransposon Reverse Transcriptase Inhibitors Role Somatic Cell Sterility Telomere Shortening Testing Time Tissue Sample Tissues Translating Traumatic injury United States National Institutes of Health analog articular cartilage bone cartilage degradation clinical practice disability drug development early onset effective therapy experimental study gait examination in vivo in vivo Model innovation joint destruction microCT mouse model novel strategies nucleoside inhibitor overexpression response senescence

项目摘要

Abstract Osteoarthritis (OA) is a degenerative joint disease involving articular cartilage degradation, chronic inflammation, and bone remodeling. Although it is a leading cause of disability in the elderly, there is no FDA approved disease modifying osteoarthritis drugs (DMOADs) currently. The scientific challenge is the incomplete understanding of mechanisms triggering inflammation and degeneration in the joint during aging or after injury, which hampers the development of DMOADs that can target these processes. The scientific goal of this project is to determine whether retrotransposon Long Interspersed Nuclear Element-1 (LINE-1, or L1), which is repressed in normal somatic cells but de-repressed in senescent cells during aging or after traumatic injury, contribute to aging-associated or post-traumatic OA (PTOA). We found that L1 levels are significantly elevated in human OA cartilage lesions and in cartilage joint of both aging-associated OA and PTOA mouse models. The innovative hypothesis is that, during aging and/or injury-associated OA, the cellular content of L1 retrotransposons is 1) significantly increased in the joint and 2) responsible for stimulation of SASP and inflammation that lead to joint destruction. If so, OA pathogenesis can be inhibited by repressing L1 using FDA- approved anti-viral drug nucleoside reverse transcriptase inhibitors (NRTIs). This hypothesis will be tested through two aims in the R61 Phase. The first aim is to characterize aging and injury induced L1 de-repression in the Col2a1-CreERT2; miR-365 mice capable of inducing early onset-OA and/or PTOA. It will establish whether aging, injury, or both would result in de-repression of the L1 levels in mouse joint during OA. The second aim is to determine whether NRTIs inhibit OA pathogenesis by repressing L1 levels in OA animal models in vivo. NRTI nucleoside cytidine analogue Lamivudine will be tested for its ability of inhibiting OA/PTOA in CreERT2; miR-365 mice. It will establish the efficacy and the window of intervention for NRTI to modify cartilage degeneration, bone remodeling, SASP gene expression, and movement deficiency in OA animal models in vivo. If the hypothesis is unambiguously supported by the experiments in R61 Phase, it will be further explored, through a mechanistic aim in the R33 Phase, to determine the molecular pathways by which L1 activates OA pathogenesis in OA mouse models and human OA tissues. It will establish the molecular pathways of L1 de-repression induced OA marker genes and SASP expression at the cellular level. This project represents a new and distinct direction for the field because it addresses the role of retrotransposons in OA pathogenesis for the very first time. If successful, NRTIs, which are safe and readily available, can be re-purposed for OA treatment in human. It will not only change the concepts that drive the OA research field, but also greatly impact the clinical practice of how we treat OA patients.

抽象的骨关节炎（OA）是一种退行性关节疾病，涉及关节软骨退化，慢性炎症和骨重塑。虽然它是老年人残疾的主要原因，但目前还没有 FDA 目前已批准疾病缓解骨关节炎药物（DMOAD）。科学挑战是对衰老或衰老过程中引发关节炎症和退化的机制不完全了解损伤后，这阻碍了针对这些过程的 DMOAD 的开发。科学目标该项目的目的是确定逆转录转座子长散布核元件-1（LINE-1或L1），在正常体细胞中受到抑制，但在衰老过程中或创伤后的衰老细胞中被解除抑制损伤，导致衰老相关或创伤后 OA (PTOA)。我们发现 L1 水平显着在人类 OA 软骨损伤以及与衰老相关的 OA 和 PTOA 小鼠的软骨关节中升高模型。创新的假设是，在衰老和/或损伤相关的 OA 过程中，L1 的细胞含量逆转录转座子 1) 在关节中显着增加，2) 负责刺激 SASP 和导致关节破坏的炎症。如果是这样，可以通过使用 FDA-抑制 L1 来抑制 OA 发病机制批准的抗病毒药物核苷逆转录酶抑制剂（NRTI）。这个假设将被检验 R61 阶段的两个目标。第一个目标是表征衰老和损伤引起的 L1 去抑制在 Col2a1-CreERT2 中； miR-365 小鼠能够诱导早发性 OA 和/或 PTOA。它将建立衰老、损伤或两者都会导致 OA 期间小鼠关节 L1 水平的去抑制。这第二个目标是确定 NRTI 是否通过抑制 OA 动物中的 L1 水平来抑制 OA 发病机制体内模型。 NRTI核苷胞苷类似物拉米夫定将测试其抑制能力 CreERT2 中的 OA/PTOA； miR-365 小鼠。它将确定 NRTI 的功效和干预窗口改变 OA 中的软骨退化、骨重塑、SASP 基因表达和运动缺陷体内动物模型。如果 R61 阶段的实验明确支持该假设，那么它将通过 R33 阶段的机械目标进一步探索，以确定分子途径其中 L1 激活 OA 小鼠模型和人类 OA 组织中的 OA 发病机制。它将建立 L1 去抑制诱导 OA 标记基因和细胞水平 SASP 表达的分子途径。该项目代表了该领域的一个新的、独特的方向，因为它解决了逆转录转座子首次在 OA 发病机制中发挥作用。如果成功，NRTI 是安全且容易使用的可用，可重新用于人类 OA 治疗。它不仅会改变驱动 OA 的概念研究领域，但也极大地影响了我们如何治疗 OA 患者的临床实践。