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。衰老降低轴突再生能力，同时增加轴突风险 损害赔偿。神经损伤后轴突再生失败可导致永久性身体运动 损害和各种残疾。人们对轴突再生的潜在机制知之甚少， 而且目前还没有有效的治疗方法来增强受损神经元的功能。 这项建议的目标是确定与年龄相关的轴突衰退的内在机制。 通过研究线粒体对轴突损伤和衰老的反应来进行再生。线粒体 它们的形态、运动性、数量和活动通过与神经核的交流而动态变化 宿主细胞以匹配当地对能量的需求，并维持细胞和自身的动态平衡。我们和其他人的 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 对轴突损伤的反应变化。我们未发表的研究也表明轴突再生是 受ATFS-1调控，是线粒体向细胞核逆行信号传递的关键因素 线粒体未折叠蛋白反应(MitoUPR)。调整线粒体对轴突损伤的反应可能 因此，它是轴突再生的关键决定因素。然而，我们不知道潜在的机制 这些线粒体对轴突损伤的反应及其在年龄相关性轴突衰退中的作用 再生。 为了描述这些未得到满足的需求，我们将结合我们在线虫遗传学、线粒体方面的专业知识 生物学，和体内激光轴突切断术在单一轴突分辨率。具体地说，我们将使用体内成像方法 监测轴突损伤后和损伤后线粒体的轴突转运和线粒体UPR的活性 在短期和长期范围内的老龄化。我们还将使用体内和体外检测来定量地 测量由轴突损伤信号和mitoUPR(目的)改变的线粒体的生理特性 1)。我们将使用基于激光的轴突切断术和遗传学方法来实验改变 检测衰老动物的线粒体与轴突再生能力的相关性(目标2)。最后，我们将表演 基于视觉的遗传方法，以发现介导线粒体定位和 神经元的交通(目标3)。 我们认为，这些办法将对维持 在衰老和损伤中通过调节线粒体功能来调节神经系统在衰老中的最佳功能 神经元。我们的发现将为恢复神经元功能的新治疗方法提供更好的见解 在神经损伤后。

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 Our unpublished studies also suggest that axon regeneration is regulated by ATFS-1, a key factor in the retrograde signaling from mitochondria to nucleus that mediates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.