Homeostatic Neuroprotection in the Aging Nervous System

衰老神经系统的稳态神经保护

• 批准号: 10633619
• 负责人: GRAEME W DAVIS
• 金额: $ 61.56万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-15 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10633619
• 关键词: Acceleration; Adult; Adverse effects; Age; Aging; Anatomy; Antibodies; Behavior; Biochemical; Cognitive; Data; Development; Disease Progression; Drosophila genus; Future; Genes; Genetic; Health; Human; In Situ; Injury; Integrins; Knock-out; Life Style; Longevity; Maintenance; Mediating; Molecular; Motor; Mouse Strains; Mus; Muscle; Muscle denervation procedure; Muscle function; Muscular Atrophy; Mutation; Nervous System; Neurodegenerative Disorders; Neurologic; Neuromuscular Junction; Onset of illness; Paper; Physiological; Process; Publishing; Quality of life; Research; Risk Factors; Rodent Model; Role; Semaphorin-3A; Semaphorins; Signal Transduction; Synapses; Testing; Therapeutic; adverse outcome; age effect; age related; aged; aging population; combat; diet and exercise; epithelial Na+ channel; frailty; mouse model; muscle form; nervous system disorder; neuromuscular; neuromuscular function; neuromuscular system; neuroprotection; neurotransmitter release; normal aging; novel; novel marker; pharmacologic; preservation; presynaptic; resilience; sarcopenia; synaptic function; tool

ABSTRACT In humans, an age-related decline in neuromuscular function is associated with loss of muscle mass (sarcopenia), increased frailty and a degradation of both health and quality of life. The only known treatments are life-style based, including exercise and diet. Rodent models have been used to demonstrate age-related changes at the neuromuscular junction (NMJ) including the fragmentation, remodeling and eventual denervation of muscle. As eloquently stated by Joshua Sanes and Jeff Lichtman, “A key feature of the adult NMJ is that it is remarkably stable under ordinary circumstances yet capable of remodeling” when perturbed by injury or age. “This combination of stability and malleability implies that synaptic maintenance is controlled actively, yet little is known about the underlying molecular mechanisms”. This is where we have recently advanced the field. In a recently published paper we demonstrate the power of homeostatic plasticity to preserve neuromuscular anatomy and function with dramatic effects on organismal health, behavior and lifespan. We refer to this as “Homeostatic Neuroprotection”. We propose to determine whether homeostatic neuroprotection counteracts the insidious effects of age-related neuromuscular decline over the normal lifespan of mice. This will be achieved by characterizing three independent mouse strains across the lifespan. We provide strong preliminary data supporting an evolutionarily conserved role for all three genes in the mechanisms of presynaptic homeostatic plasticity and accelerated aging in the mouse neuromuscular system. Age is one of the most important risk factors for nearly all neurodegenerative disorders. This line of research may underscore the general relevance of homeostatic neuroprotection as a future therapeutic avenue to ameliorate the adverse effects of age and neurological disease.

抽象的 在人类中，神经肌肉功能与年龄相关的下降与肌肉质量的丧失有关 （肌肉减少症），健康和生活质量的脆弱和降解。唯一已知的治疗方法 是基于生活方式的，包括运动和饮食。啮齿动物模型已用于证明与年龄有关 神经肌肉连接（NMJ）的变化，包括碎片，重塑和最终 肌肉的神经。正如约书亚·萨内斯（Joshua Sanes）和杰夫·利希特曼（Jeff Lichtman）雄辩的那样，“成人的关键特征 NMJ是，在普通情况下它非常稳定，但在受到重塑时” 受伤或年龄。 “稳定性和锻造性的结合意味着控制着突触维护 积极地，对基本分子机制知之甚少”。这是我们最近拥有的地方 提前了领域。在最近发表的论文中，我们证明了稳态可塑性的力量 保留神经肌肉解剖结构和功能，对有机健康，行为和 寿命。我们将其称为“稳态神经保护”。我们建议确定稳态是否 神经保护抵消了与正常的年龄相关神经肌肉下降的阴险作用 小鼠的寿命。这将通过表征整个寿命中的三种独立的小鼠菌株来实现。 我们提供了强大的初步数据，该数据支持了所有三个基因的进化配置角色 小鼠神经肌肉系统中突触前稳态可塑性和加速衰老的机制。 年龄是几乎所有神经退行性疾病的最重要危险因素之一。这条研究线 可以强调稳态神经保护作为未来治疗途径的一般意义 改善年龄和神经系统疾病的不利影响。