Nrf2 Activation for Treatment of Osteoporosis

Nrf2 激活治疗骨质疏松症

基本信息

批准号：
9766185
负责人：
JILIANG LI
金额：
$ 17.33万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
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：
2018-08-20 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9766185
关键词：
Affect Aging Animal Model Animals Antioxidants Ascorbic Acid Atherosclerosis Bed rest Binding Biomechanics Bone Density Bone Resorption Bone Tissue C57BL/6 Mouse Cell Nucleus Cells Chronic Kidney Failure Clinical Clinical Treatment Cysteine Cytosol Diabetes Mellitus Disease Estrogens Exhibits Gene Expression Profile Genes Goals Hereditary nephritis Homeostasis Intervention LoxP-flanked allele Mechanics Mediating Menopause Metabolic Bone Diseases Modeling Molecular Mus Nitric Oxide Donors Nitroglycerin Osteoblasts Osteocytes Osteogenesis Osteoporosis Outcome Oxidants Oxidation-Reduction Patients Pharmacology Phase III Clinical Trials Phenotype Pilot Projects Production Property Proteins Response Elements Role Series Serum Markers Signal Transduction Skeleton Space Flight Syndrome Tail Suspension Testing Therapeutic Effect Tissues Wild Type Mouse analog bone bone cell bone fragility bone loss bone mass bone preservation diabetic insight mineralization novel nuclear factor-erythroid 2 prevent pulmonary arterial hypertension response skeletal skeletal tissue

项目摘要

Osteoporosis affects millions of patients each year in the U.S. The clinically available agents, currently used to treat osteoporosis and bone fragility syndrome, are still limited. Estrogen loss at menopause and during aging leads to accumulation of reactive oxidant species (ROS). Mechanical unloading during long term bed rest or space flight also increase intracellular ROS production and cause bone loss. Although antioxidants, such as nitric oxide donor nitroglycerin and N-acetyl-cysteine have shown some positive effects on estrogen deficiency or unloading induced bone loss, no potent antioxidants have been developed to target on bone metabolic diseases. We have recently identified a novel target that regulates anti-oxidative response and is involved in load-induced osteogenesis and bone homeostasis. The novel target is nuclear factor erythroid 2-related factor 2, known as Nrf2. Several previous studies including ours have shown Nrf2 helps to preserve bone mass during normal and disease conditions. Recently, a synthetic Nrf2 activator, Bardoxolone Methyl (BARD), which has been used to treat diabetes associated atherosclerosis and diabetic chronic kidney diseases in animal models, is currently in Phase III clinical trials. Our long-term goal is to determine whether targeting Nrf2 by pharmacological intervention can be used to treats osteoporosis. Our preliminary findings leading to this application support the hypothesis that Nrf2 activation in osteocytes by pharmacological intervention may prevent or restore bone loss caused by unloading or estrogen deficiency through reducing ROS. We propose the following two specific aims using C57BL/6 mice as well as the Nrf2-/- floxed mice bred with Col2.3kB Col1α1-Cre or DMP1-8kb-Cre mice toward deletion of Nrf2 in osteoblastic cells or osteocytes, respectively. We will determine whether activation of Nrf2 by pharmacological intervention prevents or restores bone loss in unloading or estrogen deficient conditions; We will also determine the cellular and molecular mechanisms of Nrf2 signaling in skeletal tissues. Successful completion of this project will demonstrate potential of Nrf2 activator used to treat osteoporosis and identify the bone cells responsible for Nrf2-mediated mechanisms involved in bone formation. The project will further provide new insights in mechanosensitivity of bone cells and skeletal adaptation, and has potential to discover novel targets for osteoporosis therapy.

骨质疏松症每年在美国影响数百万的患者治疗骨质疏松症和骨脆性综合征仍然有限。更年期和衰老期间的雌激素损失导致反应性氧化物物种（ROS）的积累。长期休息期间的机械卸载或太空飞行还会增加细胞内ROS的产生并导致骨质流失。虽然抗氧化剂，例如一氧化氮的供体硝酸甘油和N-乙酰基半胱氨酸对雌激素缺乏表现出一些积极影响或卸载诱发的骨质流失，尚未开发出潜在的抗氧化剂来靶向骨代谢疾病。我们最近确定了一个调节抗氧化反应的新目标，并参与负载引起的成骨和骨稳态。新的目标是核因子红细胞2相关因子 2，称为NRF2。先前的一些研究包括我们的NRF2有助于保存骨骼在正常和疾病条件下。最近，合成的NRF2激活剂Bardoxolone甲基（BARD），它已用于治疗动物中的动脉粥样硬化和糖尿病慢性肾脏疾病的糖尿病模型目前正在III期临床试验中。我们的长期目标是确定是否针对NRF2 药理干预可用于治疗骨质疏松症。我们的初步发现导致了这一点应用支持以下假设：药物干预中的骨细胞中的NRF2激活可能通过减少ROS来防止或恢复由卸载或雌激素缺乏引起的骨质流失。我们建议以下两个特定目标使用C57BL/6小鼠以及用Col2.3KB繁殖的NRF2 - / - Floxed小鼠 COL1α1-CRE或DMP1-8KB-CRE小鼠分别在成骨细胞或骨细胞中删除NRF2。我们将确定药物干预激活NRF2是否可以防止或恢复卸载或雌激素缺乏条件；我们还将确定细胞和分子机制骨骼组织中的NRF2信号传导。成功完成该项目将证明NRF2的潜力激活剂用于治疗骨质疏松症和识别负责NRF2介导的机制的骨细胞参与骨形成。该项目将进一步提供有关骨细胞机械敏感性和的新见解。骨骼适应，并且有可能发现骨质疏松疗法的新靶标。