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.

项目概要/摘要。 作为一名高级VA研究职业科学家，我工作的总体重点是研究 氧化应激和线粒体功能障碍与年龄有关的条件，如肌肉减少症和虚弱， 以及神经变性疾病肌萎缩侧索硬化症（ALS）。我的研究项目 与退伍军人事务部的使命有关，因为肌肉减少症和虚弱对老年退伍军人的普遍影响， 以及退伍军人中渐冻人症患病率的增加。肌肉减少症是肌肉质量的进行性损失， 随着年龄的增长，肌肉数量和质量逐渐下降，导致逐渐丧失 以及体力和力量的下降。肌肉减少症对人口老龄化有着重要影响 和老年退伍军人（超过40%的退伍军人年龄超过65岁），因为福尔斯的风险增加， 受伤，导致发病率和死亡率过高。对环境中的因素和相互作用的理解 参与运动神经元健康、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是 关键是要确定潜在的治疗目标，以防止或减少肌肉萎缩在老化过程中， 神经肌肉退行性疾病，如ALS。在我最近完成的退伍军人管理局绩效评估项目中 我们专门调查了“测试NMJ破坏导致肌肉减少症的机制” 神经肌肉接头和神经支配的丧失在肌肉萎缩和无力中的作用。使用 我们测试了几种新的小鼠模型，以单独靶向神经元，单独靶向肌肉或靶向两种组织中的缺陷， 神经肌肉接头的改变是否通过调节NMJ在肌肉减少症中起关键作用 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， 肌肉中的路径。这些研究的关键发现表明，神经元的变化很重要， 可能引发肌肉的变化，但神经元和肌肉的缺陷都需要启动 完全少肌症表型。重要的是，我们进一步证明了挽救神经元缺陷 特别是在CuZnSOD（Sod 1-/-）敲除小鼠的神经元中， 肌肉减少症足以保留神经肌肉接头和骨骼肌结构，尽管高 在这个模型中的整体氧化应激水平。这些结果表明，在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起着关键作用， 如果它们针对运动神经元，可能是最有效的。研究的另一个关键结果是 在过去的资助期间，我们的新研究的基础是， 钙作为下游肌肉退行性变化的潜在调节剂。我们发现， 在Sod 1-/-小鼠模型中，可以使用SERCA的激活剂来预防肌肉质量和功能 在收缩后将钙从胞浆返回肌浆网的ATP酶泵。 我们假设，干预激活SERCA ATP酶和改善钙稳态， 骨骼肌或运动神经元可以减少衰老中的肌肉萎缩和虚弱。这是重点 我最近资助的VA Merit赠款，我们乐观地认为这些研究将建立潜在的新的 干预措施，以保持肌肉质量和功能的老年退伍军人。总之，长期目标 我的研究项目是确定肌肉纤维损失和肌肉萎缩的潜在机制。 并确定运动神经元和肌肉在NMJ中的相对贡献 退化和与年龄相关的肌肉萎缩以及与神经肌肉变性相关的疾病。 我的目标是确定潜在的干预措施，以提高肌肉质量和力量，在老年退伍军人， 以积极的方式促进健康寿命和生活质量的提高。