Roles of a novel MAPKKK in axonal responses to injury in the mammalian CNS

 描述(申请人提供)：中枢神经系统(CNS)损伤后轴突生长受限是人类脊髓损伤后功能恢复不佳或有限的主要原因。虽然早期的研究强调了神经元-外部机制的重要性，但最近该领域的发展强调了神经元对中枢神经系统损伤后轴突生长和再生的内在控制的中心作用。在神经元内源性调节因子中，有一些因子可以感知和调节损伤信号，从而在不同的神经元群体中引发不同的反应。最近在线虫和果蝇等模式生物中的发现表明，MAP激酶(MAPKKK，或MAP3K)DLK在轴突退化和再生中发挥关键作用。哺乳动物有两种序列同源物：DLK(也称为MAP3K12)和LZK(也称为MAP3K13)。一些研究表明，哺乳动物的DLK/MAP3K12在损伤后的轴突反应中起重要作用。对另一个同源基因LZK/MAP3K13知之甚少。我们的初步研究有力地表明LZK调节轴突生长。在这里，我们检验了LZK是哺乳动物神经系统损伤后轴突反应的重要调节因子的假设。我们将在不同的损伤模型中测试LZK的功能丧失和功能获得的遗传操作的效果。在此背景下，我们还将通过组合的遗传操作来检查DLK和LZK之间的任何功能冗余或协同作用。为此，我们在小鼠中产生了DLK和LZK的功能等位基因的丢失和获得。我们将用中枢神经系统中的一些损伤模型来研究损伤诱导的轴突退化、再生(损伤神经元的轴突生长)和萌发(非损伤神经元的轴突生长)，并辅之以PNS(周围神经系统)的损伤模型。最后，我们将研究LZK和DLK信号通路与轴突生长的其他神经元内在调节因子(如PTEN)之间的潜在相互作用。综上所述，这些研究将揭示LZK和DLK信号的内源性作用，并评估激活LZK和DLK信号在促进中枢神经系统损伤后轴突修复方面的治疗潜力。

 DESCRIPTION (provided by applicant): The limited axonal growth after central nervous system (CNS) injury is the principal cause of no or limited functional recovery after spinal cord injury in humans. While earlier studies emphasized the importance of neuron-extrinsic mechanisms, recent development in the field highlighted the central role of neuron-intrinsic control of axon growth and regeneration after CNS injury. Among neuron-intrinsic regulators, there are factors that sense and mediate the injury signals to elicit diverse responses in differen neuronal populations. Recent discoveries in model organisms such as the nematode and the fruit fly indicate a critical role for a MAP kinase kinase kinase (MAPKKK, or MAP3K), DLK, in axon degeneration and regeneration. There are two sequence homologues in mammals: DLK (also known as MAP3K12) and LZK (also known as MAP3K13). Several studies indicate that mammalian DLK/MAP3K12 is important in axonal responses to injury. Little is known about the other homologue LZK/MAP3K13. Our preliminary studies strongly indicate that LZK regulates axon growth. Here we test the hypothesis that LZK is an important regulator of axonal responses to injury in the mammalian nervous system. We will test the effect of loss of function and gain of function genetic manipulations of LZK in different injury models. In this context, we will also examine any functional redundancy or synergy between DLK and LZK by combined genetic manipulations. To this end, we have generated both loss and gain of function alleles for DLK and LZK in mice. We will examine injury-induced axon degeneration, regeneration (axonal growth from injured neurons) and sprouting (axonal growth from uninjured neurons) with a number of injury models in the CNS, supplemented by injury models in the PNS (peripheral nervous system). Finally, we will examine potential interaction between the LZK and DLK signaling pathways with other neuron- intrinsic (e.g. PTEN) regulators of axon growth. Together, these studies will reveal the endogenous role of the LZK and DLK signaling, and assess the therapeutic potential of activating LZK and DLK signaling in promoting axonal repair after CNS injury.