Dual treatment of sarcopenia and osteoarthritis with a Nrf2 activator

使用 Nrf2 激活剂双重治疗肌肉减少症和骨关节炎

• 批准号: 9535030
• 负责人: Karyn L Hamilton
• 金额: $ 22.8万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9535030
• 关键词: Acceleration; Address; Advocate; Affect; Age; Aging; Anti-inflammatory; Antioxidants; Biology of Aging; Cartilage; Cavia; Characteristics; Data; Degenerative polyarthritis; Development; Disease; Disease Progression; Elderly; Evaluation; Goals; Health; Histologic; Human; Impairment; Individual; Inflammation; Institutes; Intervention; Lead; Longevity; Maintenance; Mission; Mitochondria; Modeling; Morphology; Muscle function; Muscular Atrophy; Musculoskeletal; Outcome; Oxidative Stress; Pathogenesis; Pathway interactions; Population; Positioning Attribute; Preventive Intervention; Process; Protein Biosynthesis; Public Health; Recording of previous events; Research; Rodent Model; Skeletal Muscle; Testing; Therapeutic; Time; Translating; Translations; Treatment Efficacy; age related; age-related muscle loss; cellular targeting; disability; healthspan; human model; human subject; improved; improved mobility; innovation; muscle strength; novel; novel therapeutics; pre-clinical; prevent; primary outcome; programs; protein degradation; proteostasis; sarcopenia; sex; translation to humans; treatment strategy

Project Summary: PAR-15-190 seeks to accelerate the pace of development of novel therapeutics for pre- venting health issues affecting the elderly. This project proposes to simultaneously treat the age-related loss of muscle function (sarcopenia) and osteoarthritis (OA). Traditionally, studies to prevent the onset of sarcope- nia and OA in human subjects are complicated by prolonged and unpredictable development/progression of the disease. This project advocates the use of a novel guinea pig model that rapidly and predictably develops naturally-occurring/spontaneous sarcopenia and OA in a manner similar to humans. The suggested treatment strategy, which targets both sarcopenia and OA, is important and logical because: 1) both conditions are pri- mary contributors to age-related loss in mobility and functional independence, 2) loss of muscle strength and OA often occur concurrently, and 3) both disorders have shared pathogenesis involving inflammation and oxi- dative stress. The long-term goal of this project is to translate previous studies focused on the basic biology of aging into viable human treatments to slow age-related impairments. The goal of this current project is to use a Nrf2 activator to slow the progression of age-related loss in muscle function and primary OA in a guinea pig model of accelerated musculoskeletal aging. The central hypothesis is that, by targeting pathways that result in the maintenance of proteostasis over time, it will be possible to slow the onset/progression of sarcopenia and primary OA. The hypothesis is supported by data indicating that: 1) maintained proteostasis is a shared characteristic of multiple slowed-aging rodent models, 2) treatment with a Nrf2 activators increases proteostatic processes in skeletal muscle, and 3) treatment with a Nrf2 activator has been shown to be safe and viable long-term treatments as demonstrated by the National Institutes of Aging (NIA) Interventions Testing Program (ITP). To accomplish these goals, the following specific aim is proposed: to examine the potential of long-term treatment with a Nrf2 activator (PB125) for preventing the onset/progression of sarcopenia and primary OA, and the age-related decline in mobility. The primary outcome of the project is improved mobility, which will be supported by mitochondrial function, histological, morphological, and proteostatic outcomes to determine slowed progression of OA and sarcopenia. This contribution is significant because sarcopenia and OA are two leading causes of age-associated disability that often occur concurrently, and treatments that effectively slow their progression are lacking. The proposed research is innovative in that it: 1) proposes an approach that treats both conditions simultaneously by targeting common mechanisms of pathogenesis, 2) uses a treatment that targets endogenous mechanisms, 3) uses a treatment with demonstrated efficacy in extending lifespan and presumably healthspan, and 4) demonstrates the efficacy of this treatment in a model that closely models the human condition, albeit in a shorter period of time. Therefore, the project accomplishes the goal estab- lished by NIA in PAR-15-190 to accelerate the pace of development of novel therapeutics for older individuals.

项目摘要：PAR-15-190 旨在加快针对预发性癌症的新型疗法的开发步伐。 发泄影响老年人的健康问题。该项目建议同时处理与年龄相关的损失 肌肉功能（肌肉减少症）和骨关节炎（OA）。传统上，预防肌瘤发生的研究 人类受试者的 nia 和 OA 因长期且不可预测的发展/进展而变得复杂 这种疾病。该项目提倡使用一种新型豚鼠模型，该模型可以快速且可预测地发展 以与人类相似的方式自然发生/自发性肌肉减少症和 OA。建议的治疗方法 针对肌肉减少症和 OA 的策略非常重要且合乎逻辑，因为：1）这两种情况都是优先的 玛丽导致与年龄相关的活动能力和功能独立性丧失，2）肌肉力量丧失和 OA 经常同时发生，并且 3) 两种疾病具有共同的发病机制，涉及炎症和氧化 与格重音。该项目的长期目标是将先前专注于基础生物学的研究转化为 衰老成为可行的人类治疗方法，以减缓与年龄相关的损伤。当前项目的目标是使用 一种 Nrf2 激活剂，可减缓豚鼠年龄相关的肌肉功能丧失和原发性 OA 肌肉骨骼加速老化模型。中心假设是，通过靶向导致 随着时间的推移维持蛋白质稳态，将有可能减缓肌肉减少症的发作/进展 和初级 OA。该假设得到了数据的支持，表明：1）维持蛋白质稳态是一种共享的机制。 多种延缓衰老啮齿动物模型的特征，2) 用 Nrf2 激活剂治疗可增加蛋白质抑制 骨骼肌中的过程，以及 3) Nrf2 激活剂治疗已被证明是安全可行的 美国国家老龄化研究所 (NIA) 干预测试计划证明了长期治疗 （ITP）。为了实现这些目标，提出以下具体目标：研究长期潜力 使用 Nrf2 激活剂 (PB125) 治疗以预防肌肉减少症和原发性 OA 的发作/进展， 以及与年龄相关的活动能力下降。该项目的主要成果是改善流动性，这将 由线粒体功能、组织学、形态学和蛋白质静态结果支持来确定 减缓 OA 和肌肉减少症的进展。这一贡献意义重大，因为肌肉减少症和 OA 是两种疾病 经常同时发生的与年龄相关的残疾的主要原因，以及有效减缓的治疗方法 他们缺乏进步。拟议的研究具有创新性，因为它：1）提出了一种方法 通过针对共同的发病机制同时治疗这两种疾病，2) 使用一种治疗方法 针对内源性机制，3) 使用已被证明有效延长寿命的治疗方法 以及大概的 healthspan，以及 4) 在一个密切模拟的模型中证明了这种治疗的功效 人类的状况，尽管是在较短的时间内。因此，该项目实现了既定目标 NIA 在 PAR-15-190 中提出，旨在加快针对老年人的新型疗法的开发步伐。