Molecular and genetic studies of NMNAT2 in neuroprotection

NMNAT2 神经保护作用的分子和遗传学研究

• 批准号: 8813962
• 负责人: HUI-CHEN LU
• 金额: $ 2.31万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8813962
• 关键词: Address; Adult; Aging; Alzheimer' s Disease; American; Animal Model; Biochemical; Biochemical Genetics; Biochemistry; Biological Assay; Biological Models; Blood - brain barrier anatomy; Brain; Cell Death; Cells; Cerebral cortex; Charcot-Marie-Tooth Disease; Complementary DNA; Deterioration; Dose; Drug Targeting; Enzymes; FTD with parkinsonism; Glutamate-ammonia-ligase adenylyltransferase; Glutamates; Goals; Half-Life; Health; Hippocampus (Brain); Histology; Homologous Gene; Human; Human Cell Line; Image; Injury; Knowledge; Lead; Life; Maintenance; Modeling; Molecular; Molecular Chaperones; Molecular Genetics; Morphology; Mus; Nerve Degeneration; Nervous system structure; Neuraxis; Neurodegenerative Disorders; Neuroglia; Neuronal Dysfunction; Neurons; Neurophysiology - biologic function; Nicotinamide Mononucleotide; Parkinson Disease; Patients; Peripheral Nervous System; Phosphoric Monoester Hydrolases; Play; Process; Protein Isoforms; Protein phosphatase; Proteins; Role; Staining method; Stains; Stress; Structure; Sum; System; Tauopathies; Therapeutic Intervention; Tissues; Toxin; Transgenic Mice; Up-Regulation; Validation; Vincristine; Viral Vector; Work; axonal degeneration; axonopathy; base; drug discovery; environmental stressor; high throughput screening; in vivo; insight; mouse model; multi-photon; mutant; nerve injury; neuroprotection; overexpression; programs; protective effect; public health relevance; repaired; small molecule; small molecule libraries; synaptic function; tau Proteins; therapy development; vector

DESCRIPTION (provided by applicant): Proper brain function requires an active maintenance program to sustain neuronal health. In essence, neurons and glia have to repair the damage that is induced by neuronal activity, injury, toxins, and aging. Environmental stressors impact the nervous system and lead to neuronal dysfunction and degeneration if the protective mechanisms are weakened. Recent studies revealed that NMNATs (nicotinamide mononucleotide adenylyl transferase) maintain neuronal integrity and facilitate proper neural function throughout life. NMNAT2 is the major NMNAT isoform expressed in the mammalian brain and is extremely labile with a short half-life in neurons. We and others have found that NMNAT2 levels are significantly reduced in CNS tissues from patients with Alzheimer's disease, tauopathies, or Parkinson's disease. Reducing NMNAT2 function in mice leads to axonal deterioration, while NMNAT2 overexpression offers neuroprotection. In the proposed work we will address three specific aims: How does NMNAT2 reduce toxic tau species and protect neurons against tauopathy? Is NMNAT2 required to maintain neuronal health in adult brains? Is small molecule up-regulation of NMNAT2 levels neuroprotective? A combination of molecular/biochemical, genetic, anatomical, electrophysiological, imaging, viral vector and high-throughput screening approaches will be employed to accomplish these aims. This study will provide insight into how NMNAT2 maintains neuronal health in mature brains. NMNATs are potential drug targets for therapeutic interventions in neurodegeneration. A detailed knowledge on how NMNAT2 maintain neuronal integrity and its role in neuroprotection is critical not only for understanding normal brain function, but will also provide necessary insights to assist in drug discovery.

描述（由申请人提供）：适当的大脑功能需要积极的维护计划来维持神经元健康。从本质上讲，神经元和神经胶质细胞必须修复由神经元活动、损伤、毒素和衰老引起的损伤。环境压力因素影响 如果保护机制减弱，就会导致神经元功能障碍和变性。最近的研究表明，NMNAT（烟酰胺单核苷酸腺苷酸转移酶）可维持神经元完整性并促进整个生命周期的正常神经功能。 NMNAT2 是在哺乳动物大脑中表达的主要 NMNAT 亚型，并且极其不稳定，在神经元中的半衰期很短。我们和其他人发现，阿尔茨海默病、tau蛋白病或帕金森病患者的中枢神经系统组织中的 NMNAT2 水平显着降低。减少小鼠中的 NMNAT2 功能会导致轴突恶化，而 NMNAT2 过度表达则提供神经保护作用。在拟议的工作中，我们将解决三个具体目标：NMNAT2如何减少有毒的tau蛋白种类并保护神经元免受tau蛋白病？ NMNAT2 是维持成人大脑神经元健康所必需的吗？ NMNAT2 水平的小分子上调是否具有神经保护作用？将采用分子/生化、遗传学、解剖学、电生理学、成像、病毒载体和高通量筛选方法的组合来实现这些目标。这项研究将深入了解 NMNAT2 如何维持成熟大脑中的神经元健康。 NMNAT 是神经退行性疾病治疗干预的潜在药物靶点。详细了解 NMNAT2 如何维持神经元完整性及其在神经保护中的作用不仅对于理解正常大脑功能至关重要，而且还将为协助药物发现提供必要的见解。