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一个主动维护计划来维持神经元健康。本质上，神经元和神经胶质必须修复神经元活性，损伤，毒素和衰老造成的损害。环境压力源影响 如果保护机制削弱，神经系统并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转移酶）保持神经元完整性并促进一生的适当神经功能。 NMNAT2是在哺乳动物大脑中表达的主要NMNAT同工型，在神经元中的半衰期短，非常不稳定。我们和其他人发现，来自阿尔茨海默氏病，陶氏病或帕金森氏病的患者的中枢神经系统组织中NMNAT2水平大大降低。降低小鼠的NMNAT2功能会导致轴突恶化，而NMNAT2过表达可提供神经保护作用。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物种并保护神经元免受tauopathy的侵害？维持成人大脑的神经元健康是否需要NMNAT2？ NMNAT2水平的小分子上调神经保护吗？将采用分子/生化，遗传学，解剖学，电生理，成像，病毒载体和高通量筛选方法的组合来实现这些目标。这项研究将洞悉NMNAT2如何保持成熟大脑的神经元健康。 NMNAT是神经退行性治疗干预措施的潜在药物靶标。关于NMNAT2如何保持神经元完整性及其在神经保护中的作用的详细知识不仅对于理解正常的大脑功能至关重要，而且还将提供必要的见解以帮助药物发现。