IDENTIFYING THE NMNAT AXON PROTECTION PATHWAY VIA MULTIPLE SCREENING PARADIGMS

描述（由申请人提供）：轴突变性是许多神经系统疾病的共同特征，包括神经退行性疾病、遗传性神经病、创伤性损伤、糖尿病、青光眼和化疗诱导的神经毒性。轴突功能障碍是许多这些疾病的早期事件，因此轴突保护疗法是开发这些疾病新疗法的中心焦点。最近的研究表明，轴突变性是一个积极的和高度调节的过程，但内在的，神经元的机制，促进变性知之甚少。Nmnat的表达是迄今为止确定的最有效的轴突保护策略。Nmnat在哺乳动物和果蝇中保护轴突的能力表明它调节了一种基本的、进化上保守的轴突变性途径。然而，这一途径的身份是未知的。我们已经在哺乳动物神经元和果蝇中开发了新的大规模筛选模式，这将使我们能够识别Nmnat依赖性轴突保护所需的基因以及促进损伤后轴突变性的基因。我们建议探索这些新的检测方法的潜力，以确定对预防轴突变性至关重要的基因，因此，在轴突病是主要贡献者的神经系统疾病中可能具有治疗潜力。通过进行这些互补的遗传筛选，我们希望确定一个更大的群体的基因参与进化上保守的轴突变性过程比可能会发现使用任何单独的屏幕。我们期望这些探索性研究的结果将使我们的实验室以及世界各地的其他实验室在理解疾病中轴突损失的过程方面取得快速进展。 公共卫生相关性：这项研究与公共卫生有关，因为它将确定在损伤和疾病后促进轴突变性的途径的组成部分。轴突变性是许多神经系统疾病的重要组成部分，包括神经变性疾病、遗传性神经病、创伤、糖尿病、青光眼和化疗诱导的神经毒性。识别轴突中促进变性的通路的组分将提供对轴突变性的基本机制以及以轴突变性为特征的许多神经系统疾病的潜在治疗靶点的见解。

DESCRIPTION (provided by applicant): Axonal degeneration is a common feature of many neurological diseases including neurodegenerative disorders, hereditary neuropathies, traumatic injury, diabetes, glaucoma, and chemotherapy-induced neurotoxicity. Axonal dysfunction is an early event in many of these disorders, and so axo-protective therapies are a central focus for the development of new treatments for these conditions. Recent studies demonstrate that axonal degeneration is an active and highly regulated process, yet the intrinsic, neuronal mechanism promoting degeneration is poorly understood. Expression of Nmnat is the most potent axo-protective strategy yet identified. The ability of Nmnat to protect axons following a wide range of insults in both mammals and Drosophila indicates that it modulates a fundamental, evolutionarily conserved axonal degeneration pathway. However the identity of this pathway is unknown. We have developed novel, large-scale screening paradigms in both mammalian neurons and Drosophila that will allow us to identify genes required for Nmnat-dependent axonal protection as well as genes that promote axonal degeneration following injury. We propose to explore the potential of these new assays to identify genes that are crucial for the prevention of axonal degeneration and, as such, may have therapeutic potential in neurological disorders where axonopathy is a major contributor. By performing these complementary genetic screens, we hope to identify a larger cohort of genes involved in the evolutionarily conserved axonal degeneration process than would likely be found using any individual screen. It is our expectation that findings derived from these exploratory studies will allow our labs as well as others throughout the world to make rapid progress in understanding the process of axonal loss in disease. PUBLIC HEALTH RELEVANCE: This research is relevant to public health because it will identify components of pathways that promote axonal degeneration following injury and disease. Axonal degeneration is a prominent component of many neurological disorders including neurodegenerative diseases, hereditary neuropathies, trauma, diabetes, glaucoma, and chemotherapy-induced neurotoxicity. Identifying components of the pathways in axons that promote degeneration will provide insights into the fundamental mechanism underlying axonal degeneration as well as potential therapeutic targets for the many neurological diseases characterized by axonal degeneration.