Exploring the role of Phosphodiesterase 4A in axonal regeneration

探索磷酸二酯酶 4A 在轴突再生中的作用

• 批准号: 7333450
• 负责人: Benjamin D Sachs
• 金额: $ 2.47万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2009-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7333450
• 关键词: Adverse effects; Animals; Axon; Clinic; Complex; Corticospinal Tracts; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Disinhibition; Drug Delivery Systems; Elevation; Environment; Enzymes; Failure; Fellowship; Genetic; Individual; Injury; Intervention; Intracellular Second Messenger; Life; Membrane; Molecular; Molecular Target; Mus; Myelin; NGFR Protein; Natural regeneration; Nerve Regeneration; Nervous system structure; Neuraxis; Neurites; Neurodegenerative Disorders; Neurons; PDE4A4; Pathway interactions; Patients; Peptides; Play; Protein Isoforms; Recovery of Function; Regulation; Reporting; Research; Resistance; Role; Rolipram; Second Messenger Systems; Signal Pathway; Signal Transduction; Spinal cord injury; Testing; Therapeutic Intervention; Tissues; United States; axon regeneration; cAMP-specific phosphodiesterase 4A5; disability; improved; in vivo; inhibitor/antagonist; nerve injury; novel; phosphodiesterase IV; phosphoric diester hydrolase; receptor; receptor binding; repaired; rho

DESCRIPTION (provided by applicant): The failure of the Central Nervous System (CNS) axons to regenerate has been attributed primarily to the presence of inhibitory components within CNS environment that bind receptors on axons to stimulate inhibitory signaling cascades. Given that elevation of cyclic AMP (cAMP), a ubiquitous intracellular second messenger, enhances nerve regeneration and overcomes the inhibition of neurite outgrowth, molecules that regulate cAMP in neurons are prime candidates for molecular intervention in the context of nervous system repair. Indeed, rolipram, an inhibitor of type four phosphodiesterases (PDE4s), the enzymes responsible for cAMP degradation, has been shown to overcome the inhibition of neurite outgrowth (28). However, rolipram is a general inhibitor of all PDE4s (PDE4A-D) and causes many side effects in patients that preclude its use in the clinic. To treat patients effectively, a more specific inhibitor with fewer side effects is required. To date, the specific PDE4 isoforms that are targets for rolipram in the disinhibition of neurite outgrowth remain to be determined. Our major hypothesis is that phosphodiesterase 4A (PDE4A) plays a major role in the regulation of cAMP after nerve injury and is an attractive target for therapeutic intervention in neurodegenerative diseases, such as spinal cord injury. Our preliminary data indicate that: 1. Expression of the p75 neurotrophin receptor (p75NTR), a receptor implicated in the inhibition of neurite outgrowth and nerve regeneration, leads to decreased cAMP levels in neurons. 2. Inhibition of PDE4s with rolipram rescues the p75NTR induced decrease in cAMP. 3. PDE4A5 forms a complex with p75NTR and targets cAMP degradation to the membrane. 4. The extreme C-terminus of PDE4A5 directly interacts with the intracellular domain of p75NTR. In the research proposed in this fellowship application, we will determine the role of PDE4A in regulating the inhibition of neurite outgrowth (Specific Aim 1). We will examine the role of PDE4A in the regulation of both cAMP and Rho signaling, two intersecting pathways known to play major roles in the inhibition of neurite outgrowth (Specific Aim 2). We will extend these studies by examining the role of PDE4A in axonal regeneration in vivo (Specific Aim 3). There are an estimated 250,000 individuals with permanent disabilities resulting from spinal cord injuries living in the United States with 11,000 new injuries reported every year. At present, there are no effective pharmacologic agents that promote complete functional recovery after injury. The identification of novel, specific drug targets, such as PDE4A, could greatly enhance our ability to overcome the inhibition of axonal regeneration that proves so costly for victims of spinal cord injury.

描述（由申请人提供）：中枢神经系统（CNS）轴突再生失败主要归因于CNS环境中存在抑制性成分，这些成分与轴突上的受体结合以刺激抑制性信号级联。鉴于循环 AMP (cAMP)（一种普遍存在的细胞内第二信使）的升高可增强神经再生并克服神经突生长的抑制，因此调节神经元中 cAMP 的分子是神经系统修复中分子干预的主要候选者。事实上，咯利普兰是四型磷酸二酯酶 (PDE4)（负责 cAMP 降解的酶）的抑制剂，已被证明可以克服对神经突生长的抑制 (28)。然而，咯利普兰是所有 PDE4 (PDE4A-D) 的通用抑制剂，会给患者带来许多副作用，从而妨碍其在临床上的使用。为了有效地治疗患者，需要一种副作用更少的特异性更强的抑制剂。迄今为止，咯利普兰解除神经突生长抑制作用的具体 PDE4 亚型仍有待确定。我们的主要假设是磷酸二酯酶 4A (PDE4A) 在神经损伤后 cAMP 的调节中发挥着重要作用，并且是神经退行性疾病（例如脊髓损伤）治疗干预的一个有吸引力的靶点。我们的初步数据表明： 1. p75 神经营养蛋白受体 (p75NTR)（一种参与抑制神经突生长和神经再生的受体）的表达导致神经元中 cAMP 水平降低。 2.用咯利普兰抑制PDE4可以挽救p75NTR诱导的cAMP减少。 3. PDE4A5 与 p75NTR 形成复合物，并将 cAMP 降解到膜上。 4. PDE4A5的最末端C末端直接与p75NTR的胞内结构域相互作用。在本次奖学金申请中提出的研究中，我们将确定 PDE4A 在调节神经突生长抑制中的作用（具体目标 1）。我们将研究 PDE4A 在 cAMP 和 Rho 信号传导调节中的作用，这两条交叉通路已知在抑制神经突生长中发挥主要作用（具体目标 2）。我们将通过检查 PDE4A 在体内轴突再生中的作用来扩展这些研究（具体目标 3）。据估计，美国有 250,000 名因脊髓损伤而导致永久性残疾的人居住在美国，每年报告新受伤人数 11,000 例。目前，尚无有效的药物可以促进损伤后功能的完全恢复。识别新的、特定的药物靶点，例如 PDE4A，可以极大地增强我们克服轴突再生抑制的能力，事实证明，轴突再生抑制对于脊髓损伤的患者来说代价高昂。