Molecular intersection between neuronal apoptosis and axon degeneration

描述（由申请人提供）：轴突的选择性变性发生在神经元发育过程中，也见于许多神经变性情况。然而，神经元究竟如何激活和划分这种退化途径以破坏其轴突而不使细胞的其他部分处于危险之中尚不清楚。了解轴突丢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细胞凋亡途径与介导轴突特异性变性的途径之间的分子交叉。Caspase-6最近被证明在变性轴突中具有活性。这项提议将测试的假设，胱天蛋白酶-6积极促进轴突特异性死亡，通过刺激依赖性机制，涉及组件的内在（线粒体）凋亡途径。第一个目标是研究Caspase-6作为轴突变性的一般机制的重要性。具体而言，将在体外和体内的轴突变性的多种模型中检查胱天蛋白酶-6活化。重要的是，微流控技术将被用来定位对轴突的损伤，因此允许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组分的重要性（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活化中的作用。这一目标也将测试的假设，XIAP，内源性抑制剂的半胱天冬酶，保护神经元细胞体的轴突变性过程中，通过限制半胱天冬酶活性的轴突。

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.