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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：
10019329
负责人：
QIAN CHEN
金额：
$ 38.45万
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/10019329
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 meniscus injury 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.

摘要