Understanding the role of mitochondria in the age-related decline in axon regeneration

轴突再生是神经损伤后恢复神经系统的重要过程之一 和神经退化衰老降低了轴突再生能力，同时增加了轴突再生的风险。 损害赔偿神经损伤后轴突再生的失败可导致永久性的身体运动 残疾和各种残疾。关于轴突再生的基本机制知之甚少， 并且没有有效的治疗方法来增强受损神经元的功能。 这个提议的目的是确定一个内在的机制，轴突与年龄相关的下降 通过研究线粒体对轴突损伤和衰老的反应来研究再生。线粒体 动态变化的形态，运动性，数量和活动，通过与核的沟通， 以满足局部能量需求并维持细胞及其自身的稳态。我们的和其他人的 最近的研究发现轴突再生能力和线粒体行为之间存在明显的联系 对轴突损伤的反应。我们未发表的研究还表明，轴突再生是 由ATFS-1调节，ATFS-1是从线粒体到细胞核的逆行信号传导中的关键因子， 线粒体未折叠蛋白反应（mitoUPR）。调整线粒体对轴突损伤的反应， 因此是轴突再生的关键决定因素。然而，我们不知道其潜在的机制， 这些线粒体对轴突损伤的反应以及它们在与年龄相关的轴突衰退中的作用 再生 为了描述这些未满足的需求，我们将联合收割机结合我们在C.线虫遗传学，线粒体 生物学和在单个轴突分辨率下的体内激光轴突切断术。具体来说，我们将使用体内成像方法 监测轴突损伤后和损伤过程中线粒体的轴突运输和mitoUPR的活性， 在短期和长期尺度上的老化。我们还将使用体内和体外测定来定量地 测量被轴突损伤信号和mitoUPR改变的线粒体的生理特性（Aim 1）。我们将使用基于激光的轴突切断术和遗传方法实验性地改变 老化动物中的线粒体，以测试与轴突再生能力的相关性（目的2）。最后，我们将表演 基于视觉的遗传学方法来发现介导线粒体定位的遗传机制， 神经元的交通（目标3）。 我们认为，这些方法将使人们对维持这些机制有一个新的理解。 通过调节衰老和损伤过程中的线粒体功能， 神经元我们的研究结果将为恢复神经功能的新治疗方法提供更好的见解 神经损伤后。

Axon regeneration is one of the essential processes that restore the nervous system after nerve injury and neurodegeneration. Aging decreases axon-regeneration capacity while increasing the risk of axonal damages. Failure of axonal regeneration following nerve injury can lead to permanent body-movement impairment and various disabilities. Very little is known about the underlying mechanism of axon regeneration, and there is no efficient treatment to enhance the function of damage neurons. The goal of this proposal is to identify an intrinsic mechanism underlying the age-related decline of axon regeneration by investigating the responses of mitochondria to axonal damage and aging. Mitochondria dynamically change in their morphology, motility, number, and activity by communicating with the nucleus of the host cell to match local demand for energy and to maintain cellular and their own homeostasis. Our and others' recent studies have found a clear link between axon-regeneration capacity and mitochondrial behavioral changes in response to axonal damage. Our unpublished studies also suggest that axon regeneration is regulated by ATFS-1, a key factor in the retrograde signaling from mitochondria to nucleus that mediates mitochondrial unfolded protein response (mitoUPR). Adjusting mitochondrial response to axonal damage could therefore be a critical determinant of axon regeneration. We do not know, however, the underlying mechanisms of these mitochondrial responses to axonal damage and their roles in the age-related decline of axon regeneration. To delineate these unmet needs, we will combine our expertise in C. elegans genetics, mitochondrial biology, and in vivo laser axotomy at a single axon resolution. Specifically, we will use in vivo imaging approaches to monitor the axonal trafficking of mitochondria and the activity of mitoUPR after axonal damage and during aging on short-term and long-term scales. We will also use both in vivo and in vitro assays to quantitatively measure the physiological properties of mitochondria that are altered by axonal injury signals and mitoUPR (Aim 1). We will use a laser-based axotomy and genetic approaches experimentally to change the nature of mitochondria in aging animals to test the correlation with axon regeneration ability (Aim 2). Finally, we will perform visual-based genetic approaches to discover a genetic mechanism that mediates mitochondrial localization and traffic in neurons (Aim 3). We believe that these approaches will achieve a new understanding of the mechanisms that maintain optimal function of the nervous system during aging by regulating mitochondrial function in aging and injured neurons. Our findings will provide better insight into novel therapeutic approaches to restore neuronal function after nerve injury.