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）轴突再生的故障主要归因于CNS环境中抑制性成分的存在，该抑制性成分在轴突上结合受体以刺激抑制性信号级联。鉴于循环AMP（CAMP）的升高是一种无处不在的细胞内第二信使，可以增强神经再生并克服神经突生长的抑制作用，在神经元中调节cAMP的分子是在神经系统修复的上下文中进行分子干预的主要候选者。实际上，洛里普拉姆（Rolipram）是一种导致营地降解的酶的四型磷酸二酯酶（PDE4S）的抑制剂，已被证明可以克服神经突生长的抑制作用（28）。但是，Rolipram是所有PDE4S（PDE4A-D）的一般抑制剂，在无法在诊所中使用的患者中引起许多副作用。为了有效治疗患者，需要更较少的副作用的更特异性的抑制剂。迄今为止，在神经突生长抑制作用方面是rolipram的特定PDE4同工型。我们的主要假设是，磷酸二酯酶4A（PDE4A）在神经损伤后的调节中起主要作用，并且是神经退行性疾病（例如脊髓损伤）治疗干预的有吸引力的靶标。我们的初步数据表明：1。p75神经营养蛋白受体（p75NTR）的表达，这是一种与神经突生长和神经再生有关的受体，导致神经元的cAMP水平降低。 2。用rolipram抑制PDE4S挽救了P75NTR诱导的cAMP下降。 3。PDE4A5形成一个带有P75NTR的复合物，并将cAMP降解为膜。 4。PDE4A5的极端C末端直接与P75NTR的细胞内结构域相互作用。在该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的作用（特定目标1）。我们将研究PDE4A在CAMP和RHO信号传导调节中的作用，这两种相交的途径已知在抑制神经突生长中起主要作用（特定的目标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（特定目标3）。据估计，每年报告的脊髓损伤造成了25万名永久残疾人，每年报告11,000例新伤害。目前，尚无有效的药理学剂可以促进受伤后完全的功能恢复。鉴定新型的特定药物靶标，例如PDE4A，可以极大地增强我们克服抑制轴突再生的能力，这对于脊髓损伤的受害者来说是如此昂贵。