IDENTIFYING THE NMNAT AXON PROTECTION PATHWAY VIA MULTIPLE SCREENING PARADIGMS

描述(申请人提供)：轴突变性是许多神经疾病的共同特征，包括神经退行性疾病、遗传性神经疾病、创伤、糖尿病、青光眼和化疗引起的神经毒性。轴突功能障碍是许多此类疾病的早期事件，因此轴突保护疗法是开发这些疾病新治疗方法的中心焦点。最近的研究表明，轴突退变是一个活跃的、高度调控的过程，但促进退变的内在神经机制却知之甚少。Nmnat的表达是迄今发现的最有效的轴突保护策略。在哺乳动物和果蝇中，Nmnat在受到广泛的侮辱后保护轴突的能力表明，它调控着一条基本的、进化上保守的轴突退化途径。然而，这条途径的身份尚不清楚。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范例，这将使我们能够识别依赖NmNAT的轴突保护所需的基因，以及促进损伤后轴突退化的基因。我们建议探索这些新的分析方法的潜力，以确定对预防轴突变性至关重要的基因，并因此在轴索病是主要贡献者的神经疾病中具有治疗潜力。通过进行这些互补的基因筛查，我们希望识别出参与进化保守的轴突退化过程的更大的基因队列，而不是使用任何单独的筛查。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了解疾病中轴突丢失的过程方面取得快速进展。 公共卫生相关性：这项研究与公共健康相关，因为它将确定在受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疾病的重要组成部分，包括神经退行性疾病、遗传性神经疾病、创伤、糖尿病、青光眼和化疗所致的神经毒性。识别轴突中促进退变的通路成分，将有助于深入了解轴突退变的基本机制，并为以轴突退变为特征的许多神经疾病提供潜在的治疗靶点。

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.