Project 1: Mechanisms of Nanomaterial-Cell Interactions

项目1：纳米材料-细胞相互作用机制

• 批准号: 8277234
• 负责人: JOHN Arthur FAULKNER
• 金额: $ 32.4万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8277234
• 关键词: Active Biological Transport; Affect; Age; Aging; Air Pollution; Alveolar Macrophages; Animals; Artificial nanoparticles; Attention; Biodistribution; Bioinformatics; Biological; Biological Assay; Biometry; Breathing; Cell Communication; Cell Wall; Cell physiology; Cells; Charge; Chemistry; Clathrin; Collaborations; Data; Dependence; Detection; Development; Dose; Elderly; Ensure; Environment; Event; Experimental Designs; Exposure to; Fiber; Flow Cytometry; Genes; Genetic; Genomics; Goals; Health Professional; Hospitalization; Human; Immune; In Vitro; Incidence; Infection; Inflammatory; Injury; Knockout Mice; Kupffer Cells; Ligands; Liquid substance; Lung; Lysosomes; Magnetism; Measurement; Measures; Mediating; Microscopy; Modeling; Molecular; Motor; Motor Neurons; Mus; Muscle; Muscle Fibers; Muscle Weakness; Muscular Atrophy; National Institute of Environmental Health Sciences; Natural Immunity; Nerve; Nerve Regeneration; Neurons; Organelles; Oxidative Stress; Oxides; Particulate; Pathway interactions; Pattern recognition receptor; Phagocytosis; Physiological; Physiology; Play; Polystyrenes; Population; Predisposition; Property; Public Health; Quality of life; Quantitative Structure-Activity Relationship; Reactive Oxygen Species; Regulatory Pathway; Relative (related person); Research; Research Personnel; Research Support; Resources; Risk; Role; SR-A proteins; Science; Serum Proteins; Signal Transduction; Silicon Dioxide; Skeletal Muscle; Solubility; Streptococcus pneumoniae; Stress; Structure; Superoxides; Surface; System; Testing; Time; Tissues; Transgenic Mice; Work; age related; axonal sprouting; base; biodosimetry; cell type; cellular imaging; ceric oxide; copper zinc superoxide dismutase; design; dosimetry; exposed human population; falls; feeding; frailty; high risk; in vitro Model; in vivo; innate immune function; intercellular communication; iron oxide; killings; macrophage; macrophage scavenger receptors; member; model development; mouse model; nanomaterials; neuromuscular system; oxidized lipid; particle; pathogen; programs; receptor; receptor expression; receptor function; reinnervation; research study; response; scavenger receptor; trafficking; uptake

For humans, frailty constitutes of one of the most prominent and consistent features of aging and represents the summation of the effects of muscle atrophy and weakness. For the elderly, physical frailty contributes to impaired mobility, a high risk of falling, an increased incidence of muscle injury, and a decreased quality of life. Despite considerable effort over the past decade, little progress has been made in lessening the magnitude of the problem. During our first five years of support, research on a dozen or more varieties of knockout and transgenic mice, this Program Project identified the Sodl^' mouse as a highly promising model to test the working hypothesis of Project 1 that age-related skeletal muscle atrophy results from a decrease in the total number of motor units caused by increased superoxide-mediated oxidative stress in neurons and muscles, such that: (i) oxidative stress in neurons initiates a loss of motor neurons, impairs axonal sprouting from surviving motor neurons, and inhibits nerve regeneration; and (ii) oxidative stress in muscles fibers inhibits reinnervation and contributes to decreased contractility of innervated muscle fibers. The working hypothesis will be tested through experiments on SodfA and Sod1+/+ mice, transgenic Socf7v" mice with Sod1 expression rescued only in nerves (Soc/fA(N+) mice) or muscles (Soc(7~/~(M+) mice), and tissue-specific knockout mice that lack CuZnSOD activity only in nerves (Sod1A3,4N)N) or muscles (Sod 1 A3,4^). These models allow us to test hypotheses regarding the contribution of systemic oxidative stress, as well as tissue-specific oxidative stress on the structure and function of motor nerves, muscles, motor units and muscle fibers. Genetically modified mice will be studied at 6-8 months and 18-20 months, whereas Sod1+/+ mice will be studied at 6-8, 18-20, and 28-30 months. Unique aspects of the proposed studies are the determination of motor unit properties and contractility of permeabilized single fibers from Soc/f/"mice,, null mice with tissue-specific rescue, and tissue-specific Sodl knockout mice. Furthermore, studies of the relative timing of changes in nerves and muscles that have not been undertaken previously in the same animals will be particularly illuminating for establishing cause-effect relationships of age-related changes in the neuromuscular system. Along with Projects 2 and 3, studies utilizing the very powerful mouse models listed above will determine the mechanistic role of superoxide-induced oxidative stress in muscles and nerves in age-related skeletal muscle atrophy. The Public Health significance is the necessity to understand the mechanisms underlying age-associated skeletal muscle atrophy and weakness to provide the basis for health professionals to design and implement scientifically based strategies to ensure 'successful aging' by reducing and perhaps even eliminating physical frailty in the elderly population.

对于人类而言，脆弱构成了衰老和最一致的特征之一 代表肌肉萎缩和无力的影响的总结。对于老年人，身体上的脆弱 导致流动性受损，高跌落风险，肌肉损伤的发生率增加，并且 生活质量下降。尽管在过去十年中付出了巨大的努力，但几乎没有取得进展 在减少问题的大小。在我们的前五年支持中，研究了十几个或 该程序项目将更多的敲除和转基因小鼠变种，将sodl^'鼠标确定为一个 高度有希望的模型，用于测试项目1的工作假设该年龄相关的骨骼肌肉 萎缩是由于由于增加而导致的电动机总数减少 超氧化物介导的神经元和肌肉中的氧化应激，因此：（i） 神经元引发运动神经元的损失，损害轴突发芽的轴突发芽 神经元，抑制神经再生； （ii）肌肉纤维中的氧化应激抑制重新支出 并导致神经纤维纤维的收缩力降低。工作 假设将通过对SODFA和SODFA和SOD1+/+小鼠的实验进行检验 SOD1表达仅在神经（SOC/FA（N+）小鼠）或肌肉（SOC（7〜/〜（M+）小鼠）和组织特异性 仅在神经（SOD1A3,4N）N）或肌肉（SOD 1 A3,4^）中缺乏cuznsod活性的敲除小鼠。这些 模型使我们能够检验有关系统性氧化应激的贡献的假设以及 组织特异性的氧化应激对运动神经，肌肉，运动单位和功能的结构和功能 肌肉纤维。转基因小鼠将在6-8个月零18-20个月中进行研究，而 SOD1+/+小鼠将在6-8、18-20和28-30个月中研究。拟议研究的独特方面是 从SOC/F/“小鼠， 带有组织特异性救援的无效小鼠和组织特异性的SODL敲除小鼠。此外，研究 神经和肌肉变化的相对时机以前尚未进行 动物将特别阐明，以建立与年龄相关的变化的因果关系 在神经肌肉系统中。除了项目2和3，利用非常强大的鼠标的研究 上面列出的模型将确定超氧化物诱导的肌肉中氧化应激的机械作用 和与年龄有关的骨骼肌萎缩的神经。公共卫生意义是必要 了解与年龄相关的骨骼肌萎缩和无力的机制 卫生专业人员设计和实施基于科学的策略的基础，以确保 通过减少，甚至可以消除老年人口的身体脆弱来“成功衰老”。