BLR&D Research Career Scientist Award Application

BLR

• 批准号: 10618299
• 负责人: HOLLY VAN REMMEN
• 金额: --
• 依托单位: OKLAHOMA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10618299
• 关键词: ATP phosphohydrolase; Acceleration; Address; Age; Age Years; Aging; Amyotrophic Lateral Sclerosis; Atherosclerosis; Atrophic; Award; Biology; Cachexia; Calcium; Caring; Coupling; Cytosol; Data; Degenerative Disorder; Denervation; Deterioration; Diabetes Mellitus; Disease; Elderly; Fracture; Functional disorder; Funding; Gastrocnemius Muscle; General Population; Generations; Goals; Grant; Health; Homeostasis; Impairment; Injury; Institutionalization; Intervention; Journals; Knockout Mice; Maintenance; Malignant Neoplasms; Measures; Mediating; Mediator; Mission; Mitochondria; Modeling; Morbidity - disease rate; Motor Neurons; Mus; Muscle; Muscle Fibers; Muscle Weakness; Muscle function; Muscular Atrophy; Myopathy; Nerve; Neurodegenerative Disorders; Neuromuscular Junction; Neurons; Obesity; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Phenotype; Physical Function; Physiology; Play; Population; Prevalence; Process; Publishing; Pulmonary Emphysema; Pump; Quality of life; Reactive Oxygen Species; Research; Research Support; Role; SOD2 gene; Sarcoplasmic Reticulum; Scientist; Skeletal Muscle; Superoxides; Testing; Therapeutic; Tissues; Traction; United States Department of Veterans Affairs; Veterans; Wild Type Mouse; Work; age related; age-related muscle loss; aging population; career; copper zinc superoxide dismutase; deconditioning; demographics; design; effective intervention; fall risk; falls; frailty; healthspan; human old age (65+); improved; insight; military veteran; mitochondrial dysfunction; mortality; mouse model; muscle form; muscular structure; nerve supply; neuromuscular; novel; oxidative damage; pharmacologic; physically handicapped; postsynaptic; preservation; presynaptic; prevent; programs; restoration; sarcopenia; superoxide dismutase 1; synaptic function; therapeutic target

Project Summary/Abstract. The overall focus of my work as a Senior VA Research Career Scientist has been to study the effect of oxidative stress and mitochondrial dysfunction in age-related conditions such as sarcopenia and frailty, and in the neurodegenerative disease, Amyotrophic Lateral Sclerosis (ALS). My research program is highly relevant to the mission of the VA due to the universal impact of sarcopenia and frailty on older veterans, and the increased prevalence of ALS in veterans. Sarcopenia is the progressive loss of muscle mass and function with age characterized by a deterioration of muscle quantity and quality leading to a gradual loss of activity and a decline in strength and power. Sarcopenia has a critical impact on the aging population and older Veterans (more than 40% of veterans are over age 65) due to the increased risk of falls and injuries, leading to excess morbidity and mortality. An understanding of the factors and interactions in the mechanisms involved in motorneuron health, maintenance and eventual degeneration of the neuromuscular junction (NMJ), synaptic function and degenerative changes in the muscle tissue itself are critical to identify potential therapeutic targets to prevent or reduce muscle atrophy during aging and in neuromuscular degenerative diseases such as ALS. In my most recent completed VA merit review project “Testing the mechanisms by which NMJ disruption contributes to sarcopenia” we specifically investigated the role of the neuromuscular junction and loss of innervation in muscle atrophy and weakness. Using several novel mouse models to target deficits in neurons alone, muscle alone or in both tissues, we tested whether alterations in the neuromuscular junction play a critical role in sarcopenia by modulating the NMJ through presynaptic and postsynaptic alterations and measuring the effect on downstream degenerative pathways in muscle. Key findings from these studies show that changes in the neuron are important, and likely initiate changes in the muscle, yet deficits in both the neuron and the muscle are required to initiate a full sarcopenic phenotype. Importantly, we further demonstrated that rescuing neuronal deficits specifically in neurons in a CuZnSOD (Sod1-/-) knockout mouse that mimics accelerated age related sarcopenia is sufficient to preserve neuromuscular junction and skeletal muscle structure despite the high levels of overall oxidative stress in this model. These results suggest that redox homeostasis in motor neurons plays a key role in initiating sarcopenia during aging and that therapies to reduce muscle atrophy during aging may be most effective if they target the motor neurons. Another key result from the studies in the past funding period formed the basis for our new studies that point to maintenance of cytosolic calcium as a potential regulator of downstream muscle degenerative changes. We found that the loss of muscle mass and function in the Sod1-/- mouse model could be prevented using an activator of the SERCA ATPase pump that returns calcium form the cytosol to the sarcoplasmic reticulum following contraction. We hypothesized that interventions to activate the SERCA ATPase and improve calcium homeostasis in skeletal muscle or motor neurons can reduce muscle atrophy and weakness in aging. This is the focus of my recently funded VA Merit grant and we are optimistic these studies will establish potential new interventions to preserve muscle mass and function in aging veterans. In summary, the long term goals for my research program are to determine the underlying mechanisms of muscle fiber loss and muscle weakness with aging and to define the relative contributions of the motor neuron and muscle in NMJ deterioration and age-related muscle atrophy and diseases associated with neuromuscular degeneration. I aim to identify potential interventions to improve muscle quality and strength in older veterans and contribute in a positive way to increased healthspan and quality of life.

项目摘要/摘要。 作为退伍军人管理局高级研究职业科学家，我工作的总体重点是研究 与年龄相关的疾病（如肌肉减少症和虚弱）中的氧化应激和线粒体功能障碍， 在神经退行性疾病、肌萎缩侧索硬化症（ALS）方面，我的研究项目非常重要。 由于肌少症和虚弱对老年退伍军人的普遍影响，与退伍军人管理局的使命相关， 退伍军人中肌萎缩性侧索硬化症（Sarcopenia）的患病率增加是指肌肉质量的逐渐丧失。 随着年龄的增长，功能会随着肌肉数量和质量的下降而逐渐丧失 活动减少以及力量和力量的下降对人口老龄化具有重大影响。 和老年退伍军人（超过 40% 的退伍军人年龄超过 65 岁），因为跌倒和摔倒的风险增加 伤害，导致过高的发病率和死亡率。 了解其中的因素和相互作用。 涉及运动神经元健康、维持和最终退化的机制 神经肌肉接头（NMJ）、突触功能和肌肉组织本身的退行性变化 对于确定潜在的治疗靶点以预防或减少衰老过程中的肌肉萎缩至关重要 在我最近完成的 VA 绩效评估项目中。 我们专门调查了“测试 NMJ 破坏导致肌肉减少症的机制” 神经肌肉接头的作用和神经支配丧失在肌肉萎缩和无力中的作用。 我们测试了几种针对单独神经元、单独肌肉或两种组织缺陷的新型小鼠模型 神经肌肉接头的改变是否通过调节 NMJ 在肌肉减少症中发挥关键作用 通过突触前和突触后的改变并测量对下游退行性变的影响 这些研究的主要发现表明，神经元的变化很重要，并且 可能会引发肌肉的变化，但需要神经元和肌肉的缺陷来启动 重要的是，我们进一步证明了挽救神经缺陷。 特别是在 CuZnSOD (Sod1-/-) 敲除小鼠的神经元中，该小鼠模拟加速衰老相关的现象 肌肉减少症足以保护神经肌肉接头和骨骼肌结构，尽管 该模型中的总体氧化应激水平这些结果表明运动中的氧化还原稳态。 神经元在衰老过程中引发肌肉减少症中发挥着关键作用，并且减少肌肉萎缩的疗法 研究的另一个关键结果是，如果它们针对运动神经元，则在衰老过程中可能最有效。 在过去的资助期间形成了我们新研究的基础，该研究指出维持细胞质 我们发现钙作为下游肌肉退行性变化的潜在调节剂。 使用 SERCA 激活剂可以预防 Sod1-/- 小鼠模型中的肌肉质量和功能 ATP 酶泵在收缩后将细胞质中的钙返回至肌浆网。 我们培养了这种干预措施来激活 SERCA ATP 酶并改善钙稳态 骨骼肌或运动神经元可以减少衰老过程中肌肉萎缩和无力。 我最近资助了 VA 优异奖助学金，我们乐观地认为这些研究将建立潜在的新 总之，长期目标是保持老年退伍军人的肌肉质量和功能。 我的研究计划是确定肌纤维损失和肌肉的潜在机制 衰老导致的无力，并定义运动神经和肌肉在 NMJ 中的相对贡献 恶化和与年龄相关的肌肉萎缩以及与神经肌肉变性相关的疾病。 我的目标是确定潜在的干预措施，以提高老年退伍军人的肌肉质量和力量 为延长健康寿命和提高生活质量做出积极贡献。