Regenerative and Degenerative Responses to Axonal Injury

描述(申请人提供)：再生医学的一个重要目标是了解神经元如何感知和反应轴突损伤。由于轴突高度极化的结构，轴突运输机械将细胞货物从轴突的一个部分运送到另一个部分，在细胞对损伤的反应中发挥着重要作用。一个主要的反应是诱导新的轴突生长。这种再生反应需要信号分子从损伤部位逆行运输到细胞核。另一个主要反应是被切断的远端‘残肢’的退化。这也可能依赖于轴突运输机制，因为在神经退行性疾病中，轴突运输过程中的缺陷通常伴随(并经常继续)轴突变性。为了研究损伤信号、退化和轴突运输的机制，我们利用果蝇强大的遗传学作为模式生物，开发了一种新的损伤范式，可以在体内对损伤反应途径进行机械表征。我们的分析包括核记者，它测量受损神经元中基因表达的变化，以及实时成像分析，测量轴突中特定货物的轴突运输。本研究的重点是一种保守的轴突激酶，在果蝇中称为Wallenda(WND)，在脊椎动物中称为DLK的作用和机制。最近的研究表明，该激酶调节轴突损伤的再生和退行性反应。我们最近的观察表明，WND可能通过调节轴突中特定货物的运输而发挥作用。本研究的目标是识别WND调控的货物，并确定这种货物在逆行信号和退化中的作用(S)。

DESCRIPTION (provided by applicant): An important goal for regenerative medicine is to understand how neurons sense and respond to axonal damage. Due to the highly polarized structure of axons, axonal transport machinery, which delivers cellular cargo from one part of the axon to the other, plays important roles in the cellular responses to injury. One major response is the induction of new axonal growth. This regenerative response requires the retrograde transport of signaling molecules from the injury site to the nucleus. Another major response is degeneration of the severed distal 'stump'. This may also rely on axonal transport machinery, since defects in the process of axonal transport usually accompany (and often proceed) axonal degeneration in neurodegenerative disorders. To study mechanisms of injury signaling, degeneration, and axonal transport, we take advantage of the powerful genetics of Drosophila as a model organism, in which we have developed a new injury paradigm that allows mechanistic characterization of injury response pathways in vivo. Our assays include nuclear reporters, which measure changes in gene expression in injured neurons, and live imaging assays that measure axonal transport of specific cargo in axons. The focus of this study is the role and mechanism of a conserved axonal kinase, named Wallenda (Wnd) in Drosophila, DLK in vertebrates. Recent studies indicate that this kinase regulates both regenerative and degenerative responses to axonal injury. Our recent observations suggest that Wnd may function by regulating the transport of specific cargo in axons. The goals of this study are to identify the Wnd-regulated cargo, and determine the role(s) of this cargo in both retrograde signaling and degeneration.