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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.

在美国，骨质疏松症每年影响数百万患者。临床上可用的药物目前用于治疗骨质疏松症和骨脆综合症，仍然有限。更年期和衰老过程中雌激素的流失导致活性氧化剂（ROS）的积累。长期卧床期间机械卸载或太空飞行还会增加细胞内活性氧的产生并导致骨质流失。虽然抗氧化剂，例如一氧化氮供体硝酸甘油和 N-乙酰半胱氨酸对雌激素缺乏症显示出一些积极作用或卸载引起的骨质流失，目前尚未开发出有效的抗氧化剂来针对骨代谢疾病。我们最近发现了一个调节抗氧化反应的新靶点，并参与负荷诱导的成骨和骨稳态。新靶点是核因子红细胞2相关因子 2，称为Nrf2。之前的几项研究（包括我们的研究）已表明 Nrf2 有助于保持骨量在正常和疾病条件下。最近，一种合成的 Nrf2 激活剂，巴多索隆甲基 (BARD)，已用于治疗动物糖尿病相关的动脉粥样硬化和糖尿病慢性肾病模型，目前正在进行 III 期临床试验。我们的长期目标是确定是否通过药物干预可用于治疗骨质疏松症。我们的初步调查结果导致了这一点应用支持这样的假设：药物干预可能会激活骨细胞中的 Nrf2 通过减少ROS来预防或恢复因卸荷或雌激素缺乏引起的骨质流失。我们建议使用 C57BL/6 小鼠以及用 Col2.3kB 培育的 Nrf2-/- floxed 小鼠实现以下两个具体目标 Col1α1-Cre 或 DMP1-8kb-Cre 小鼠分别在成骨细胞或骨细胞中缺失 Nrf2。我们将确定通过药物干预激活 Nrf2 是否可以预防或恢复骨丢失卸荷或雌激素缺乏的情况；我们还将确定其细胞和分子机制骨骼组织中的 Nrf2 信号传导。该项目的成功完成将展示 Nrf2 的潜力用于治疗骨质疏松症并鉴定负责 Nrf2 介导机制的骨细胞的激活剂参与骨形成。该项目将进一步提供骨细胞机械敏感性的新见解骨骼适应，并有可能发现骨质疏松症治疗的新靶点。