Promoting axon regeneration by activation of the Smad1 signaling pathway

通过激活 Smad1 信号通路促进轴突再生

• 批准号: 8485698
• 负责人: Hongyan Zou
• 金额: $ 32.16万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8485698
• 关键词: Acute; Address; Adult; Afferent Neurons; Age; Area; Axon; Axotomy; Biological Assay; Brain; C-terminal; Chronic; Clinical Treatment; Clinical Trials; Complement; Data; Down-Regulation; Effectiveness; Emotional; Genes; Goals; Growth; In Vitro; Injection of therapeutic agent; Injury; Laboratories; Lesion; Ligands; MAP Kinase Gene; MAPK8 gene; Mediating; Methods; Modeling; Molecular; Molecular Target; Motor; Multiple Trauma; Mus; Mutant Strains Mice; Mutation; Natural regeneration; Neurologic; Neurons; Outcome; Pathway interactions; Phenotype; Phosphorylation; Phosphotransferases; Pilot Projects; Play; Recombinant adeno-associated virus (rAAV); Recovery of Function; Research; Resistance; Rodent; Rodent Model; Role; Saline; Sensory; Serine; Signal Pathway; Site; Spinal Cord; Spinal Ganglia; Spinal cord injury; Spinal cord injury patients; Testing; Therapeutic; Translating; Vertebral column; Work; age related; axon growth; axon regeneration; base; bone morphogenetic protein 4; bone morphogenetic protein receptors; clinically relevant; compare effectiveness; design; empowered; in vivo; injured; insight; instrumentation; kinase inhibitor; minimally invasive; motor control; mouse model; mutant; novel; programs; regenerative; response; transcription factor; upstream kinase

DESCRIPTION (provided by applicant): Spinal cord injury severs the connections between the brain and the spinal cord, which causes devastating outcomes such as loss of sensory and motor controls below the lesion site. The reason behind the permanent neurological deficit is that adult mammalian neurons fail to regenerate after injury. One strategy for successful axon regeneration is to enhance the intrinsic axon growth capability of injured neurons. This requires defining molecular pathways that can promote axon outgrowth and establishing therapeutic approaches to turn them on. Recently, we have demonstrated a key role of Smad1, a transcription factor, in switching adult sensory neurons into an active growth state in vitro. This proposal focuses on the in vivo function of the Smad1 pathway using rodent models of spinal cord injury. We propose to test the central hypothesis that activation of Smad1 in adult sensory neurons promotes axon regeneration of ascending sensory pathway. This hypothesis is supported by our pilot studies that demonstrate robust sensory axon regeneration with activation of Smad1 in DRGs. This was achieved using a minimally invasive and clinically applicable in vivo gene manipulation method designed in my laboratory specifically for in vivo spinal cord research. Based on these exciting results, Aim 1 will investigate the Smad1 activation mechanisms in DRG neurons. This includes BMP-dependent and -independent pathways. The role of a novel kinase, Mps1, in mediating axonal growth and the function of the differential phosphorylation of Smad1-at the linker area and C- terminus will be studied. The downstream targets of Smad1 will be identified. Aim 2 focuses on in vivo assays using rodent models of spinal cord injury to compare the regenerative phenotypes of Smad1 activation by BMP-dependent and -independent pathways. Therapeutic potential of AAV-BMP will be further evaluated by injecting AAV after injury. In summary, these studies are expected to provide insights into the therapeutic potential of manipulating the Smad1 pathway on axon regeneration after spinal cord injury. Furthermore, this proposal also aims at identifying novel molecular targets that activate Smad1 or act as downstream effectors. Finally the in vivo studies will validate a minimally invasive and clinically applicably therapeutic approach that can be readily translated into clinical trials for spinal cord injury patients.

描述（由申请人提供）：脊髓损伤切断了大脑和脊髓之间的连接，这会导致毁灭性的后果，例如损伤部位以下的感觉和运动控制丧失。永久性神经缺陷背后的原因是成年哺乳动物神经元受伤后无法再生。成功轴突再生的一种策略是增强受损神经元的内在轴突生长能力。这需要定义可以促进轴突生长的分子途径，并建立启动它们的治疗方法。最近，我们证明了转录因子 Smad1 在体外将成年感觉神经元转变为活跃生长状态中的关键作用。该提案的重点是使用脊髓损伤的啮齿动物模型来研究 Smad1 通路的体内功能。我们建议测试以下中心假设：成人感觉神经元中 Smad1 的激活促进上行感觉通路的轴突再生。这一假设得到了我们的初步研究的支持，该研究证明了 DRG 中 Smad1 的激活可实现强大的感觉轴突再生。这是通过我的实验室专门为体内脊髓研究设计的微创且临床适用的体内基因操作方法来实现的。基于这些令人兴奋的结果，Aim 1 将研究 DRG 神经元中的 Smad1 激活机制。这包括 BMP 依赖性和非 BMP 依赖性途径。将研究一种新型激酶 Mps1 在介导轴突生长中的作用以及 Smad1 在接头区域和 C 末端的差异磷酸化的功能。 Smad1 的下游靶标将被确定。目标 2 侧重于使用脊髓损伤啮齿动物模型进行体内测定，以比较 BMP 依赖性和非依赖性途径激活 Smad1 的再生表型。 AAV-BMP 的治疗潜力将通过损伤后注射 AAV 来进一步评估。总之，这些研究有望为脊髓损伤后操纵 Smad1 通路对轴突再生的治疗潜力提供见解。此外，该提案还旨在识别激活 Smad1 或充当下游效应器的新分子靶点。最后，体内研究将验证一种微创且临床适用的治疗方法，该方法可以很容易地转化为脊髓损伤患者的临床试验。