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。 作为退伍军人事务部高级研究职业科学家，我的总体工作重点是研究 与年龄相关的疾病中的氧化应激和线粒体功能障碍，如石棺减少和虚弱， 在神经退行性疾病中，肌萎缩侧索硬化症(ALS)。我的研究计划是高度 与退伍军人管理局的任务有关，因为石棺减少和虚弱对老年退伍军人的普遍影响， 退伍军人中肌萎缩侧索硬化症的发病率增加。骨质疏松症是肌肉质量的进行性下降和 随着年龄增长的功能，其特征是肌肉数量和质量的退化导致逐渐丧失 活动的减少，力量和权力的下降。骨质疏松症对老龄化人口的影响至关重要 以及年龄较大的退伍军人(超过40%的退伍军人年龄在65岁以上)，这是因为跌倒和 伤害，导致过高的发病率和死亡率。对影响因素和相互作用的理解 运动神经元的健康、维持和最终变性的机制 神经肌肉接头(NMJ)、突触功能和肌肉组织本身的退行性变化 关键是确定潜在的治疗靶点，以防止或减少在衰老和 神经肌肉退行性疾病，如肌萎缩侧索硬化症。在我最近完成的退伍军人事务部绩效评估项目中 我们专门研究了“测试NMJ破坏导致石棺减少症的机制” 神经肌肉接头和神经缺失在肌肉萎缩和无力中的作用。vbl.使用 我们测试了几种仅针对神经元、肌肉或两种组织中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在骨质疏松症中起关键作用 通过突触前和突触后的改变以及测量对下游退行性变的影响 肌肉中的通路。这些研究的关键发现表明，神经元的变化是重要的，并且 可能引发肌肉的变化，但需要神经元和肌肉的缺陷才能启动 一种完整的石蜡生成表型。重要的是，我们进一步证明了挽救神经元缺陷 特别是在模拟加速衰老相关的CuZnSOD(SOD1-/-)基因敲除小鼠的神经元中 骨质疏松症足以保存神经肌肉连接和骨骼肌结构，尽管 这一模型中的整体氧化应激水平。这些结果表明，运动中的氧化还原动态平衡 神经元在衰老过程中启动肌萎缩症起着关键作用，并通过治疗来减少肌肉萎缩 如果它们以运动神经元为靶点，那么在衰老过程中可能是最有效的。这项研究的另一个关键结果 在过去的资助期形成了我们新研究的基础，这些研究指向维持胞浆 钙作为下游肌肉退行性变化的潜在调节因子。我们发现失去的是 使用SERCA激活剂可防止SOD1-/-小鼠模型中的肌肉质量和功能 ATPase泵，收缩后将钙从胞浆返回肌浆网的泵。 我们假设，激活SERCA ATPase和改善钙稳态的干预措施 骨骼肌或运动神经元可以减少肌肉萎缩和衰老时的虚弱。这是我们关注的焦点 我最近资助的退伍军人事务部奖励金，我们乐观地认为这些研究将建立潜在的新的 保护老年退伍军人肌肉质量和功能的干预措施。总而言之，长期目标是 因为我的研究计划是确定肌肉纤维丢失和肌肉的潜在机制 NMJ中运动神经元和肌肉的相对贡献 退化和与年龄相关的肌肉萎缩以及与神经肌肉退化相关的疾病。 我的目标是确定潜在的干预措施，以改善老年退伍军人的肌肉质量和力量 以积极的方式为提高健康寿命和生活质量做出贡献。