Molecular intersection between neuronal apoptosis and axon degeneration

神经元凋亡与轴突变性之间的分子交叉

• 批准号: 8467860
• 负责人: Corey Leigh Cusack
• 金额: $ 3.14万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8467860
• 关键词: Adult; Affect; Antibodies; Apoptotic; Axon; Brain; Caspase; Caspase Inhibitor; Cells; Cessation of life; Critical Pathways; DNA Damage; Development; Disease; Grant; In Vitro; Injury; Interphase Cell; Knockout Mice; Label; Lead; Mediating; Microfluidics; Microtubules; Mitochondria; Modeling; Molecular; Nerve Degeneration; Nerve Growth Factors; Neurodegenerative Disorders; Neuronal Injury; Neurons; Pathway interactions; Play; Process; Risk; Role; Spinal Ganglia; Stimulus; Stress; System; Technology; Testing; Withdrawal; apoptotic protease-activating factor 1; axonal degeneration; caspase-3; caspase-6; caspase-9; cytochrome c; deprivation; human BIRC4 protein; in vivo; inhibitor-of-apoptosis protein; injured; nervous system development; neurofilament; neuron apoptosis; neuron development; neuron loss; neuronal cell body; novel therapeutic intervention; prevent; programs; receptor; research study; tool

DESCRIPTION (provided by applicant): Selective degeneration of axons occurs during neuronal development and is also seen in many neurodegenerative situations. However, exactly how a neuron can activate and compartmentalize this degenerative pathway to destroy its axon without putting the rest of the cell at risk is unclear. Understanding the molecular mechanism of axonal loss is important for developing new therapeutic interventions to treat axon degeneration in pathological conditions. This project will explore the molecular intersection between apoptotic pathways that destroy an entire neuron and pathways that mediate axon-specific degeneration. Caspase-6 was recently shown to be active in degenerating axons. This proposal will test the hypothesis that Caspase-6 actively contributes to axon-specific demise through a stimulus-dependent mechanism that involves components of the intrinsic (mitochondrial) apoptotic pathway. The first aim will investigate the importance of Caspase-6 as a generalized mechanism of axon degeneration. Specifically, Caspase-6 activation will be examined in multiple models of axon degeneration in vitro and in vivo. Importantly, microfluidic technology will be utilized to localize insults to axons, therefore allowing the study of axon-specific degeneration without affecting the neuronal cell body. The second aim will examine the importance of known apoptotic components (e.g., Bax, cytochrome c, Caspase-9, Apaf-1, Caspase-3) in Caspase-6 activation during axon-specific degeneration. This aim will also test the hypothesis that XIAP, an endogenous inhibitor of caspases, protects the neuronal cell body by restricting caspase activity to the axon during axonal degeneration.

描述（由申请人提供）：选择性轴突变性发生在神经元发育过程中，也见于许多神经退行性情况。然而，神经元是如何激活和划分这条退行性通路以破坏其轴突而不危及细胞其余部分的，目前尚不清楚。了解轴突损失的分子机制对于开发新的治疗干预措施来治疗病理条件下的轴突变性是重要的。该项目将探索破坏整个神经元的凋亡通路和介导轴突特异性变性的通路之间的分子交叉。最近发现Caspase-6在退化轴突中有活性。该提议将验证Caspase-6通过刺激依赖机制积极参与轴突特异性死亡的假设，该机制涉及内在（线粒体）凋亡途径的组成部分。第一个目的是研究Caspase-6作为轴突退化的一般机制的重要性。具体来说，Caspase-6的激活将在体外和体内的多种轴突变性模型中进行检测。重要的是，微流体技术将用于定位轴突的损伤，因此可以在不影响神经元细胞体的情况下研究轴突特异性变性。第二个目标将检查已知的凋亡成分（例如，Bax，细胞色素c， Caspase-9, Apaf-1, Caspase-3）在轴突特异性变性期间Caspase-6激活中的重要性。这一目的也将验证XIAP（一种内源性半胱天冬酶抑制剂）在轴突变性过程中通过限制半胱天冬酶对轴突的活性来保护神经元细胞体的假设。