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: 8699280
• 负责人: Hongyan Zou
• 金额: $ 32.99万
• 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/8699280
• 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联系，导致毁灭性的后果，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的神经元在受伤后不能再生。增强损伤神经元的内在轴突生长能力是成功实现轴突再生的策略之一。这需要确定能够促进轴突生长的分子途径，并建立治疗方法来开启它们。最近，我们已经证明了Smad1（一种转录因子）在体外将成人感觉神经元转换为活跃生长状态中的关键作用。本研究主要利用啮齿类动物脊髓损伤模型研究Smad1通路的体内功能。我们提出验证Smad1在成人感觉神经元中的激活促进上行感觉通路轴突再生的中心假设。这一假设得到了我们的初步研究的支持，这些研究表明，DRGs中Smad1的激活会使感觉轴突再生。这是通过我的实验室专门为体内脊髓研究设计的微创和临床适用的体内基因操作方法实现的。基于这些令人兴奋的结果，Aim 1将研究Smad1在DRG神经元中的激活机制。这包括依赖于bmp和不依赖于bmp的途径。将研究一种新的激酶Mps1在介导轴突生长中的作用，以及连接区和C端smad1的差异磷酸化的功能。将确定Smad1的下游靶点。目的2侧重于使用啮齿动物脊髓损伤模型进行体内实验，比较Smad1通过bmp依赖性和非依赖性途径激活的再生表型。损伤后通过注射AAV进一步评价AAV- bmp的治疗潜力。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，本提案还旨在确定激活Smad1或作为下游效应物的新分子靶点。最后，体内研究将验证一种微创和临床适用的治疗方法，可以很容易地转化为脊髓损伤患者的临床试验。