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: 7565926
• 负责人: Ana Luisa Jordao Perdigoto
• 金额: $ 2.57万
• 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/7565926
• 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）： 脊髓损伤后神经再生的缺乏归因于多种因素，必须克服所有这些因素才能实现功能恢复。中枢神经系统中存在生长抑制信号，但周围神经系统中不存在，导致中枢神经系统无法再生。脊髓再生中一个公认的障碍是损伤部位髓磷脂抑制蛋白的表达。髓磷脂抑制蛋白导致神经塌陷并远离损伤部位，从而阻止再生。这项工作将重点阐明髓磷脂抑制蛋白阻止中枢神经系统轴突再生的机制。髓磷脂抑制蛋白通过 Nogo 受体 (NgR) 发挥作用，该受体在生长的轴突表面表达，并通过与 p75 神经营养蛋白受体 (p75) 相互作用发出信号。 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 GTPases Rho 家族的信号级联反应。 p75 缺乏内在催化活性，依赖细胞内衔接蛋白发出信号，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发挥作用。我们假设 TRAF6 是 NgR-p75 复合物下游生长抑制信号转导所必需的。我们研究的具体目的是 1) 确定髓磷脂蛋白抑制轴突生长是否需要 TRAF6 2) 评估在髓磷脂抑制蛋白结合后 TRAF6 是否被 p75 招募来调节 GTPase 活性 3) 研究 TRAF6 参与抑制轴突生长的机制。将在体外和体内研究缺乏 TRAF6 的神经元的轴突生长，以确定 TRAF6 下游髓磷脂抑制蛋白的作用。使用原代神经元培养物，我们将评估 TRAF6 在 GTP 酶活性调节中的作用。我们实验室的数据表明 TRAF6 和 p21 激活激酶（一种已知的肌动蛋白细胞骨架调节剂）之间可能存在功能相互作用。我们将研究这种相互作用作为 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有价值的见解。这些知识将使我们能够制定治疗策略，促进脊髓损伤后神经元的生长，从而预防瘫痪。