Dissection of SARM1-Induced Axon Degeneration and Cell Death

项目概要/摘要： 轴突变性是一些最普遍的神经系统疾病中的早期且可能的起始事件 这些疾病包括周围神经病、创伤性脑损伤、帕金森病和青光眼。 虽然轴突缺失是许多神经系统疾病的核心，但目前还没有有效的治疗方法， 目标轴突断裂。轴突变性是一种亚细胞自我破坏的过程， 创伤性代谢性和神经退行性损伤从概念上讲，这种退化程序类似于 凋亡途径--它是一种生物化学途径，以与细胞凋亡相似的方式抑制受损的轴突。 凋亡途径协调功能障碍细胞的程序性死亡，尽管分子水平上， 机制主要不同。其他人和我们发现SARM 1是一个重要的组成部分， 损伤激活轴突变性程序。重要的是，SARM 1也需要轴突损失的模型中， 神经系统疾病，包括周围神经病变和创伤性脑损伤。因此，阻止 SARM 1活性是轴突损失疾病中轴突保存的令人兴奋的治疗候选物。在 在之前的资助期间，我们取得了重大的概念性突破，发现SARM 1是一个NAD+切割， 因此，它是轴突变性途径中的药物靶点。然而，为了充分利用 为了靶向SARM 1，我们必须了解SARM 1上游和下游的分子机制 酶活性在这里，我们将探讨SARM 1衍生的NAD+代谢产物作为生物标志物的作用， 轴突变性的介质。我们还将确定在健康轴突中保持SARM 1“关闭”的机制 并在患病轴突中开启SARM 1。如果成功，这些研究将确定分子机制 SARM 1酶活性的上游和下游，并确定新的治疗靶点 神经系统疾病中轴突的保存。

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.