Dissection of SARM1-Induced Axon Degeneration and Cell Death

项目摘要/摘要： 轴突变性是一些最常见的神经系统疾病的早期和可能的始发事件。 疾病，包括周围神经病、创伤性脑损伤、帕金森氏症和青光眼。 尽管轴突丢失是许多神经疾病的核心，但目前还没有有效的治疗方法。 目标轴突破裂。轴突变性是一种亚细胞的自毁过程，由 创伤、新陈代谢和神经退化的侮辱。从概念上讲，这种退化计划类似于 凋亡途径--这是一种生化途径，其分解受损轴突的方式与 凋亡途径协调功能障碍细胞的程序性死亡，尽管分子 机制主要是不同的。其他的，我们发现Sarm1是 损伤激活的轴突变性程序。重要的是，Sarm1也是轴突丢失所必需的。 神经系统疾病，包括周围神经疾病和创伤性脑损伤。因此，阻止 Sarm1活性是轴突丢失疾病中保留轴突的令人兴奋的候选治疗方案。在 在之前的资助期，我们在概念上取得了重大突破，发现Sarm1是NAD+裂解 因此，它是轴突退化途径中的一个可用药靶点。然而，要充分利用这一承诺 为了靶向Sarm1，我们必须了解Sarm1上下游的分子机制 酶活性。在这里，我们将探索Sarm1衍生的NAD+代谢物作为生物标志物和 轴突变性的中介物。我们还将确定使Sarm1保持在健康轴突中的机制 在患病的轴突中打开Sarm1。如果成功，这些研究将确定分子机制 Sarm1酶活性的上游和下游，并寻找新的治疗靶点 神经性疾病中轴突的保护。

Project Summary/Abstract: Axonal degeneration is an early and likely initiating event in some of the most prevalent neurological diseases, including peripheral neuropathies, traumatic brain injury, Parkinson's disease and glaucoma. Although axon loss is central to many neurological disorders, no treatments currently exist that effectively target axonal breakdown. Axon degeneration is a subcellular self-destructive process that is activated by traumatic, metabolic, and neurodegenerative insults. Conceptually this degeneration program is akin to the apoptotic pathway—it is a biochemical pathway that dismantles injured axons in much the same way that the apoptotic pathway orchestrates the programmed death of dysfunctional cells, although the molecular mechanisms are primarily distinct. Others and we discovered that SARM1 is an essential component of the injury-activated axonal degeneration program. Importantly, SARM1 is also required for axon loss in models of neurological disease, including peripheral neuropathies and traumatic brain injury. Hence, agents that block SARM1 activity are exciting therapeutic candidates for axonal preservation in diseases of axon loss. In the prior funding period we made a major conceptual breakthrough, discovering that SARM1 is a NAD+ cleaving enzyme and, hence, a druggable target in the axon degeneration pathway. However, to exploit the full promise of targeting SARM1 we must understand the molecular mechanisms upstream and downstream of SARM1 enzyme activity. Here we will explore the role of SARM1-derived NAD+ metabolites as biomarkers and mediators of axon degeneration. We will also identify the mechanisms that keep SARM1 `off' in a healthy axon and turn SARM1 `on' in a diseased axon. If successful, these studies will define the molecular mechanisms upstream and downstream of SARM1 enzyme activity and identify novel therapeutic targets for the preservation of axons in neurological diseases.