The role of TRAF6 in the regulation of neurite outgrowth

TRAF6 在神经突生长调节中的作用

• 批准号: 7408209
• 负责人: Ana Luisa Jordao Perdigoto
• 金额: $ 2.55万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7408209
• 关键词: Actins; Adaptor Signaling Protein; Axon; Binding; Biochemical Process; Complex; Cues; Cytoskeleton; Data; Family; Growth; Guanosine Triphosphate Phosphohydrolases; In Vitro; Injury; Knowledge; Laboratories; Myelin; Myelin Proteins; NGFR Protein; Natural regeneration; Nerve; Nerve Regeneration; Neuraxis; Neurites; Neurons; Paralysed; Peripheral Nervous System; Proteins; Recovery of Function; Recruitment Activity; Regulation; Research; Role; Signal Transduction; Site; Spinal cord injury; Surface; TNF receptor-associated factor 6; Therapeutic; Work; axon growth; axon regeneration; in vivo; insight; neuronal growth; p21 activated kinase; prevent; receptor; rho; spinal cord regeneration; transcriptional coactivator p75

DESCRIPTION (provided by applicant): The lack of nerve regeneration following spinal cord injury has been attributed to several factors, all of which must be overcome for functional recovery to occur. The presence of outgrowth inhibitory cues in the central nervous system, but not the peripheral nervous system, contribute to the inability of the central nervous system to regenerate. One well established obstacle in spinal cord regeneration is the expression of myelin inhibitory proteins at the site of injury. Myelin inhibitory proteins cause the nerve to collapse and retract away from the injury site, thus preventing regeneration. This work will focus on elucidating the mechanisms by which myelin inhibitory proteins prevent axon regeneration in the central nervous system. Myelin inhibitory proteins act through the Nogo receptor (NgR), which is expressed on the surface of growing axons and signals through its interaction with the p75 neurotrophin receptor (p75). The mechanisms by which NgR and p75 inhibit axon outgrowth have not been fully established. One known mechanism by which p75 inhibits axon outgrowth is through a signaling cascade involving the Rho family of GTPases. p75 lacks intrinsic catalytic activity and relies on intracellular adaptor proteins to signal, such as TNF Receptor Associated Factor 6 (TRAF6). Preliminary data from our laboratory suggests a role for TRAF6 in the inhibition of axon outgrowth by myelin inhibitory proteins. We hypothesize that TRAF6 is required for the transduction of the growth inhibitory signal downstream of the NgR-p75 complex. The specific aims of our research are to 1) Determine whether TRAF6 is required for axon outgrowth inhibition by myelin proteins 2) Evaluate whether TRAF6 is recruited by p75 following binding of the myelin inhibitory proteins to regulate GTPase activity 3) Investigate the mechanism by which TRAF6 is involved in inhibition of axon outgrowth. Axon outgrowth will be studied in neurons lacking TRAF6 both in vitro and in vivo to establish a role for TRAF6 downstream of myelin inhibitory proteins. Using primary neuron cultures, we will assess the role of TRAF6 in the regulation of GTPase activity. Data from our laboratory indicates a possible functional interaction between TRAF6 and p21-activated kinase, a known modulator of the actin cytoskeleton. We will pursue this interaction as a mechanism by which TRAF6 inhibits axonal growth. This work will provide valuable insight into the biochemical processes involved in the inhibition of nerve regeneration. This knowledge will allow us to develop therapeutic strategies to promote neuronal growth following spinal cord injury and thus prevent paralysis.

描述（由申请人提供）： 脊髓损伤后缺乏神经再生归因于几个因素，所有这些因素都必须克服，以使其发生功能恢复。中枢神经系统中但不存在外周神经系统的出现抑制线索的存在，导致中枢神经系统无法再生。脊髓再生中一个良好的障碍物是在损伤部位表达髓磷脂抑制蛋白。髓磷脂抑制蛋白会导致神经塌陷并从损伤部位缩回，从而阻止再生。这项工作将着重于阐明髓磷脂抑制性蛋白防止中枢神经系统中轴突再生的机制。髓磷脂抑制蛋白通过NOGO受体（NGR）作用，该蛋白通过与P75神经营养蛋白受体的相互作用在生长轴突和信号表面表达（p75）。 NGR和P75抑制轴突生长的机制尚未完全确定。 p75抑制轴突生长的一种已知机制是通过涉及Rho GTPases家族的信号传导级联。 p75缺乏固有的催化活性，并且依赖于信号的细胞内衔接蛋白，例如TNF受体相关因子6（TRAF6）。我们实验室的初步数据表明，Traf6在髓磷脂抑制蛋白抑制轴突生长中的作用。我们假设TRAF6是NGR-P75复合物下游的生长抑制信号所必需的。我们的研究的具体目的是1）确定髓磷脂蛋白的轴突生长抑制是否需要TRAF6。将在缺乏TRAF6的神经元和体内研究轴突生长，以确立髓磷脂抑制蛋白下游的作用。使用原发性神经元培养物，我们将评估TRAF6在GTPase活性调节中的作用。来自我们实验室的数据表明，TRAF6和P21激活激酶（肌动蛋白细胞骨架的已知调节剂）之间可能存在功能相互作用。我们将追求这种相互作用作为TRAF6抑制轴突生长的机制。这项工作将为抑制神经再生所涉及的生化过程提供宝贵的见解。这些知识将使我们能够制定治疗策略，以促进脊髓损伤后神经元生长，从而防止瘫痪。