Neuronal microtubule regulation and aging

神经元微管调节与衰老

• 批准号: 10179627
• 负责人: Lizhen Chen
• 金额: $ 31.41万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10179627
• 关键词: Address; Affect; Age; Age of Onset; Aging; Alleles; Alzheimer' s Disease; Animals; Architecture; Axon; Biochemical; Biological Process; Caenorhabditis elegans; Cells; Cytoskeleton; Data; Defect; Dendrites; Development; Disease; Elements; Functional disorder; Gap Junctions; Genes; Genetic; Goals; Growth; Intervention; Lead; Link; Lipids; Longevity; MAP4; Maintenance; Measures; Metabolic Pathway; Metabolism; Microtubule Polymerization; Microtubule Stabilization; Microtubule-Associated Proteins; Microtubules; Mitotic; Molecular; Monitor; Morphology; Mutation; Nerve Degeneration; Nervous system structure; Neurodegenerative Disorders; Neurons; Orthologous Gene; Peripheral; Play; Positioning Attribute; Process; Proteins; Regulation; Reporting; Risk Factors; Role; Signal Transduction; Structure; Testing; Time; Tissues; Transgenes; Transgenic Organisms; Tubulin; age effect; age related; age related neurodegeneration; base; confocal imaging; experimental study; genetic approach; healthy aging; imaging approach; in vivo; insight; lipid metabolism; lipidomics; loss of function; mutant; neuron loss; neuronal cell body; normal aging; novel; optogenetics; preservation; tau Proteins; tool

PROJECT SUMMARY (Neuronal microtubule regulation and its autonomous and non-autonomous effects on aging) Aging is the greatest risk factor for developing neurodegenerative diseases including Alzheimer's Disease (AD). Neuronal aging, defined as a progressive loss of function and structure, predisposes neurons to degeneration. The importance of microtubule (MT) regulation in neurons is underscored by the critical role of MT-associated proteins, e.g. tau and tau-like proteins, whose dysfunction leads to neurodegeneration. Surprisingly, little is known about the role of MTs in the normal aging process. MT regulation is involved on several levels of neuronal function and maintenance of structure, and MT regulation also appears to be a general downstream indicator and effector in age-dependent neurodegeneration. The cause and effect relationship between MT defects and cellular dysfunction is not clear. In C. elegans, it has been demonstrated that mutations in protein with tau-like repeats (ptl-1), an ortholog of tau/MAP2/MAP4, leads to defective neuronal function and an accelerated occurrence of age-associated morphological changes. On the other hand, it has also been shown that mutations in other MT regulators delay the onset of age-related changes. These data show defects in MTs are not only associated with, but also contribute to, neuronal aging. The goals of this proposed study are to define changes in MT status associated with neuronal aging and to characterize mechanisms by which MT defects affect neuronal function. Preliminary data indicate mutations in multiple MT regulators are sufficient to influence lipid metabolism and lifespan. The central hypothesis is preservation of MT polymerization in neurons delays neuronal aging and promotes longevity through gap junctions. In Aim 1, we will test whether loss of MT polymerization causes neuronal aging. In Aim 2, we will test whether neuronal MT perturbation regulates longevity and peripheral lipid metabolism via gap junctional signaling. Confocal imaging, molecular, biochemical and C. elegans genetic approaches will be used to fulfil these aims. Data generated from this proposal will not only increase our understanding of the roles played by MT regulation in the neuronal and organismal aging, but also potentially lead to novel targets to delay aging and its associated diseases.

项目摘要 （神经元微管调节及其对衰老的自主和非自主影响） 衰老是发展神经退行性疾病包括阿尔茨海默病的最大风险因素 （AD）。神经元老化被定义为功能和结构的进行性丧失， 退化微管（MT）调节在神经元中的重要性被以下关键作用所强调： MT相关蛋白，例如tau和tau样蛋白，其功能障碍导致神经变性。 令人惊讶的是，人们对MT在正常衰老过程中的作用知之甚少。MT监管涉及到 几个层次的神经元功能和结构的维持，MT调节似乎也是一个重要的机制。 年龄依赖性神经退行性变的一般下游指标和效应物。的因果 MT缺陷和细胞功能障碍之间的关系尚不清楚。In C.已经证明， 具有tau样重复序列（ptl-1）的蛋白质（tau/MAP 2/MAP 4的直系同源物）中的突变导致缺陷性 神经元功能和年龄相关的形态学变化的加速发生。另 另一方面，也有研究表明，其他MT调节因子的突变延迟了年龄相关变化的发生。 这些数据表明，MTs的缺陷不仅与神经元老化有关，而且还有助于神经元老化。的 这项拟议研究的目标是定义与神经元衰老相关的MT状态变化，并 表征MT缺陷影响神经元功能的机制。初步数据显示， 多种MT调节剂足以影响脂质代谢和寿命。核心假设是 神经元中MT聚合的保存延缓神经元老化并通过间隙促进寿命 交叉点在目标1中，我们将测试MT聚合的丧失是否导致神经元老化。在目标2中，我们将 测试神经元MT扰动是否通过间隙连接调节寿命和外周脂质代谢。 发信号。共聚焦成像、分子、生物化学和C。elegans遗传学方法将用于实现 这些目标。从这一提案中产生的数据不仅将增加我们对以下方面所发挥作用的了解： MT在神经元和生物体衰老中的调节，也可能导致新的靶点来延缓衰老 及其相关疾病。